Dr Kaushik S Bhojani, a Consultant Rheumatologist talked about the much acclaimed Stem Cell transplant treatment for Scleroderma patients at the Sclerocon e-conference held in June 2023 by Scleroderma India. Dr Bhojani clears the air on who is eligible, what to expect along with the pros and cons of opting for the transplant.
Origin of stem cells transplant as treatment option for Scleroderma
We know that the treatment of Scleroderma or systemic sclerosis, is less than satisfactory at this point in time. Most of the evidence is on Cyclophosphamide. There is some evidence for the skin and lungs with Mycophenolate and Methotrexate for the skin and the joints for those people who have arthritis secondary to systemic sclerosis. There is nothing further. We started trying Rituximab for people with bad interstitial lung disease (ILD) and we did find that there was some improvement but there isn't a concrete trial to prove that rituximab will be the answer for all the Scleroderma problems. Rituximab can be used as an option when nothing else really works. Naturally when you have a morbid disease with a decreased lifespan overall, you want to offer the patient some relief.
Stem cell therapy came up as a hope when patients of lymphoma and leukemia who also had some autoimmune diseases were given stem cell therapy, and they found that their autoimmune disease seemed to quieten down. This prompted the research 25-30 years ago about trying this independently for the patients with autoimmune diseases. Currently maximum data is available for Multiple Sclerosis and secondly for Scleroderma which is systemic sclerosis. Most of the data is not from India since we don't really have a systematic registry where we actually document every patient of systemic sclerosis or lupus or dermatomyositis who actually comes in. Currently the information comes from the international databases either the European or the American. Interestingly the European database is much more precise, while you have trials coming in from the U.S.
Full video can be seen at https://www.youtube.com/watch?v=iv45POqdghw
What is autologous stem cell transplant?
In autologous stem cell transplant the patients’ own blood is taken out, you filter the blood cells to use the positive stem cells which is done by a filtered machine called leucophoresis machine. You filter out the naive stem cells which are there and use high-dose chemotherapy to kill practically the entire immune system of the systemic sclerosis patient. In some cases total body irradiation is done - you radiate the whole body because you may not succeed completely by doing it just with chemotherapy. Then you infuse the filtered stem cells that you earlier collected from the same patient and put them back in the patient. The patient of course is in isolation and it's roughly expected that about two weeks down the road you will have some amount of regeneration of white cells coming from these fresh stem cells which go into the bone marrow. The bone marrow once again starts regenerating white cells beginning with the neutrophils and the platelets. This is the critical phase where the patient is an open target for any and every viral infection. You can presume that your stem cell transplant is now succeeding when you have had three consecutive days of the neutrophil count rising above 500. Neutrophil count is between 4000 to 7000 in a normal person but when you've burnt all the cells you're down to zero or less than a hundred. That is when you have no infection no immunity at all, and latent viruses in your body can take advantage.
There's a lot of extreme isolation; a lot of antibiotic and antiviral covers that have to be put in place. You continuously monitor twice a day how the white cells and platelets are improving. Once you reach a stage where the platelets are more than 20,000 for three consecutive days and the white cell counts are consecutively more than 500, you can expect that the white cells will now engraft themselves.
What is the purpose of doing stem cell transplant?
The purpose of doing this is reconstitution of the immune system. When you use high dose chemotherapy and irradiating the body in certain cases, you're killing away all the diseased or inflamed cells thus worsening your disease. Then you can expect that now the naive cells that you've put in are going to turn around and help improve the immune system and induce tolerance. We are seeing that there's improvement which is why the interest in stem cells has really taken taken off now not only across the globe but definitely in India as well. We are looking at the fact that more and more patients would possibly try and opt for it.
Outcome of Stem cell transplant in Scleroderma?
When you use autologous stem cell transplant, there's a significant positive response but there are a few caveats. The pre and the post is what I would really like you to understand.
The pre-part is not a completely safe procedure. You're an easy target for infections. There is also transplant related mortality, which is within the first 100 days post the transplant. Incidence for this used to be close to 10% but they have kept on improvising on that and now they claim that it's between 6-8%. Apart from the infections, the biggest risk in a Scleroderma case undergoing stem cell is transplant related mortality due to cardiac involvement. Scleroderma does affect the heart or a Scleroderma patient should not be opting for stem cell transplant if they have a compromised cardiac function.
Cardiac function evaluation
This is the first thing that you need to understand and sometimes by the time you realize that there is a cardiac involvement, it's a little late. So a screening process for the pulmonary hypertension, the right heart failure, the left heart failure etc has to be flawless. You can't rely on just a 2D ECHO or stress test, and say my cardiac function seems to be okay. Non-invasive cardiac testing may not work and so every patient with systemic sclerosis who's thinking of stem cell transplant needs to undergo right heart catheterization to get an accurate measurement of the pulmonary artery pressure. However, this is not enough, because the patient is lying down for a few hours before the right heart catheterization without exertion, so how are you going to know whether you've got a flawless procedure. You need to do a fluid challenge and check if the pulmonary artery pressure goes up. If the heart is not able to take up the fluid challenge within 10 minutes, infuse a large amount of saline and once again check. In order to check the cardiac function in terms of the microvascular perfusion, you need to do a cardiac MRI. If your reports for cardiac MRI, pulmonary hypertension and electrical activity are sorted, you can opt for transplant. High dose of cyclophosphamide, which is known to be cardiotoxic could have affected your heart during your years of use.
What to expect?
Suppose everything is successful, you expect that you're going to get better. You need to know what to expect and don't be under the impression that stem cell transplant is a cure. It is not a cure, it's not going to reverse your disease. It is the best treatment modality available to induce a remission, but what has already been damaged is damaged.
- Expect improvement in the skin for sure that's been proven. In order to confirm whether the skin improves only because it takes away the fibrosis or it takes away the inflammatory component of the fibrosis, you would have to do a skin biopsy pre and post to look at the amount of fibrosis versus the inflammation.
- The inflammation in the lung will go down, so the PFT will show improvement in terms of forced vital capacity (FVC), which is your ability to take in air. It may or may not improve the diffusion in the DLCO.
- The food pipe will improve but not necessarily.
- If you have a renal involvement going towards a deterioration, you might be able to stabilize it.
- Evidence is mild on whether calcinosis (deposition of calcium in skin and subcutaneous tissue) will go away or not, but further deterioration will not happen.
This is called expectation management. Know it's not going to be an easy process definitely in the first one year because your immune system takes months to recover. The lymphocytes are still coming up and that takes months so you are a target for infection even after you are out of the first 100 days. In the long term, you're much better off compared to what you have today. We don’t know yet if it is the go-to solution yet.
What is the expense of stem cell transplant?
Expense depends from centre to centre. The ballpark figure is usually between 12 and 15 lakhs, for scleroderma it can up to 20 lakhs, if you have complications, it can go higher. So, if you're going to spend that kind of money you must go in with a complete picture about the facts.
A longitudinal study of the patients who underwent the stem cell transplant showed that they did way better than those who did not. We don't know very clearly but in the long run the autologous hemopoietic stem cell transplant, we are finding that the data is in favour.
When to go for it?
If you have a rapidly Progressive systemic sclerosis which is progressively going downhill, and that's when you know that if you don't intervene quickly, you are going to get into trouble as far as this patient's lifespan is concerned. It is preferred is that you select patients who are in rapidly progressive disease within the first four years. Male patients have a worse prognosis the females. Patient must have a good cardiac function, pulmonary artery pressures, and mean pulmonary artery pressure of 25 or less. If you have a rapidly progressive skin disease where your Ordnance skin score is rapidly rising or is already high with a long-term prognosis which is not good. Then you would consider looking at a stem cell transplant. It is also favourable in the younger age group less than 45 years.
If you don't have a stringent selection criterion, you can land up in all sorts of complications and your outcome will be much worse.
Dr Kaushik S Bhojani
Dr Bhojani is a Consultant Rheumatologist and the Head of Rheumatology Services at Fortis Hospitals, Mumbai Cluster. With more than 20 years of experience in his field of specialisation, he has deep expertise in the treatment and management of all types of rheumatic diseases as well as auto-immune diseases. He also has a special interest in the rehabilitation of patients with disabilities due to long-standing arthritis.
MBBS from MP Shah Medical college, Jamnagar. DNB (Internal Medicine) from PD Hinduja National Hospital, Mumbai.
Note: This is a loosely edited text of the presentation made by Dr. Bhojani at the Sclerocon 2023 conference
