Can a Stem Cell Transplant Cure an Autoimmune Disease

Transcript of Presentation.

(00:00): [Thom Stewart]: Hello everyone. Welcome to the workshop Can a Stem Cell Transplant Cure an Autoimmune Disease? My name is Thom Stewart and I will be your moderator for this workshop.

(00:13): Speaker Introduction. It is my pleasure to introduce today's speaker, Dr. Ernesto Ayala. Dr. Ayala is a Hematologist-Oncologist in the Department of Internal Medicine at the Mayo Clinic in Jacksonville, Florida. He specializes in transplantation for the treatment of benign and malignant hematologic conditions and the treatment of lymphoma. He also applies new immunotherapies – including CAR T-cell therapy for the treatment of advanced lymphoma – and has an interest in the use of autologous transplantation for the treatment of severe autoimmune disorders, such as scleroderma and multiple sclerosis. Please join me in welcoming Dr. Ayala.

(01:04): [Dr. Ernesto Ayala]:  Thank you, Thom. Thanks for the kind introduction. As you said, I'm a bone marrow transplant doctor. Over the past five years, I've been working with patients who have severe autoimmune disease, and it has become a very important part of what I do.  

(01:38): Overview of Talk. Today, I'm going to briefly go over what we believe is the origin of autoimmune disease. What is the current standard treatment for autoimmune diseases? Do we use an autologous transplant or an allogeneic transplant for autoimmune disease? How does an autologous transplant work in patients with autoimmune disease? What autoimmune diseases can be treated with an autologous stem cell transplant? What factors determine if a patient with an autoimmune disease is a good candidate for transplant? Finally, I will review the short- and long-term risks and side effects of autologous transplantation.

(02:38): Let’s start with the origin of autoimmune disease. This graphic shows different ways we believe autoimmune diseases are caused. On top, we see ‘HLA cytokine pathways’, which represents factors that are inherited. There's a strong, familial tendency to develop autoimmune disease. If a person has an autoimmune disease, their family members may have an increased risk of developing another autoimmune disease.

(03:20): At the bottom, you see ‘defective regulation’. There appears to be a defect in the way the immune system functions in patients with autoimmune diseases, and some lack of coordination in those cells.

(03:36): Environmental triggers also play a role, and this includes infections, traumatic insults, and microbiome changes – or alterations of the normal bacterial flora in the bowels. Whether the autoimmune disease is inherited or due to defective cell regulation, there is always a trigger that starts the reaction.  

(04:12): I added a fourth arrow here that says ‘sex’. As we will discuss later, autoimmune diseases are far more frequent in women than in men. So, there seems to be a strong influence of hormones in the development of autoimmune disease.

(04:30): To the right, you can see that the ending consequence of all these causative factors is the formation of autoreactive T-cells. The most important cells in our immune system are the B lymphocytes and T lymphocytes. These grow, expand, become autoreactive, and start causing tissue injury and damage. This is the pathway for the development of autoimmune disease.

(05:22): Autoimmune diseases are predominantly diagnosed in young to middle aged women. In most autoimmune diseases, the ratio of females to males is approximately three or four to one, and it can reach up to nine to one with Lupus.  

(05:45): In all autoimmune diseases, antibodies and cells – including lymphocytes and macrophages – cause damage to different tissues. The B lymphocytes produce what we call ‘auto-antibodies’, which target and damage the tissues in an organ system. They can affect any organ system, and include, but are not limited to, neurological, gastrointestinal, rheumatological and endocrine.

(06:23): Some autoimmune diseases affect only one specific organ. For example, there is a condition known as Hashimoto's thyroiditis. The only organ that is affected is the thyroid. Multiple sclerosis is another example in which the target is the myelin protein. Myelin is actually a lipid that is present in the brain and the spinal cord. So, the damage is in the brain and the spinal cord.

(07:01): There are many autoimmune diseases that affect multiple organs in the body, including scleroderma, lupus, Crohn's disease, and rheumatoid arthritis. They can affect the joints, lungs, heart, and gastrointestinal tract. Some of the elements of the blood - such as red blood cells and platelets - can be affected or destroyed by the disease as well.

(07:30): There are a couple treatment options for autoimmune diseases. Corticosteroids – like prednisone and dexamethasone – are commonly used as they can rapidly decrease inflammation, and are helpful in getting a crisis or flare-up under control. However, they are not helpful for long-term treatment.

(08:00):  We now have several immunosuppressive medications as well. These are oral agents that depress the function of the immune system, and must be taken for months or years.

(08:16): More recently, we have disease modifiers. These are antibodies that target the specific pathways that activate the immune cells. These have revolutionized the treatment of autoimmune disease. You may have even seen them on TV – they're being advertised all over for Crohn's, lupus and much more.

(08:40): These treatments are all very useful, but have several limitations. They are very expensive. All these treatments must be done for many years – often lifelong – to keep the disease under control. And, there is always the risk of breakthrough. Even with the best possible treatment, the disease is resistant, resilient, and can break through.

(09:16): There are two main types of transplants – allogeneic and autologous transplants. Allogeneic transplants use stem cells from a donor. This is a definitive therapy – because you are giving new bone marrow to the patient, you are completely replacing the immune system with the new donor cells. Because of this, you will definitely eradicate the autoimmune disease.

(10:07): However, we don't frequently utilize this form of transplant because it carries a much higher risk or side effects, complications and increased mortality. Most specialists would agree an allogeneic transplant is just too risky.

(10:35): Autologous transplantation utilizes the patient's own stem cells for the transplant, and helps reset the patient’s immune response. It has a much lower risk and is effective in the majority of patients.  

(11:16): The ultimate goal of an autologous transplant is to reestablish the immune system’s ‘self-tolerance’ – our immune systems should be tolerant of our bodies and not attack our bodies. So, we attempt to reset the immune system to prevent injury to the organs in the body.  

(11:36): We do this by essentially destroying all the pathogenic auto-reactive immune cells. We destroy the lymphocytes and cells that are causing the problem, and that leads to an immunological renewal as the patient generates new cells. We call these new cells ‘naive,’ because they have not been exposed to the patient’s organs. These new naive T and B lymphocytes that will not attack the organs, and in that way the disease will become dormant.

(12:21): The transplant also seems to cause a reactivation and improvement of the thymic function as well. The thymus is a gland that helps train the cells within the immune system about what to attack and what not to attack, so this is an important aspect of transplantation as well.

(12:39): We also re-establish regulatory T-cells. T lymphocytes regulate the immune system’s activity, and can either stop or stimulate the cells as needed. By reestablishing these regulatory cells, it leads to an immunological renewal and a reset of the immune response.

(13:14): This slide provides a visual illustration on what occurs before and after an autologous transplant. The patient starts by getting a conditioning regimen – such as cyclophosphamide and anti-thymocyte globulin (CY+ATG) – a week before the transplant. The patient then gets the infusion of the stem cells. In the beginning, there is recovery of the granulocytes, followed by the generation of new, naive lymphocytes. Thymic reactivation occurs next, and these steps all allow for the reconstitution of an immune system that is going to be tolerant of the body. This is how we hope the disease will stop.

(13:57): There are many steps that occur during the pre-transplant workup and assessment, and in many ways, it's similar to any other autologous transplant. We perform testing of the heart, kidneys, liver, and lungs to understand the body’s baseline, and ensure it will be able to tolerate the transplant. There is a psychosocial assessment, and we also focus on fertility preservation, because so many are young patients wanting to protect their fertility.

(14:43):  There are some disease specific assessments as well. For example, if a patient has multiple sclerosis, we want to do an MRI of their brain and spine to get a baseline of how affected the brain is prior to transplant. Or, if it’s a patient with Crohn's disease, we want to do a colonoscopy to see the status of the disease. Different diseases will have different focused assessments, based on how the body is affected by the autoimmune disease.  

(15:11): When it is time to collect the stem cells, we give patients injections to help expand and mobilize the stem cells from the bone marrow to the bloodstream, and utilize a machine – called an apheresis machine – to collect those stem cells from the bloodstream. This picture on the right of this slide shows someone hooked up to an apheresis machine. This is a simple outpatient procedure, and is very well-tolerated.

(15:52): Now, it is finally time for the transplant.  

(15:58): Typically, patients are admitted into the hospital, and can expect to stay admitted for two to three weeks. During the first five days prior to your transplant – referred to as “day -5” to transplant day, which is “day 0” – patients undergo their conditioning regimen. The conditioning regimen is a combination of chemotherapy, and sometimes low doses of total body irradiation and antibodies. All of these are used to completely destroy the immune cells of the patient.

(16:28): This slide includes the most common combination of treatments that we use during conditioning, but there are several variations. The most common combination is a chemotherapy agent called cyclophosphamide, and Rabbit anti-thymocyte globulin (Rabbit ATG) – which is a collection of antibodies we get from rabbits. These conditioning treatments are administered during those five days prior to transplant, and we monitor the patient closely for reactions during these infusions.

(16:59): After they complete their conditioning, we reinfuse those cells that we collected back into the patient. Because the conditioning regimen has partially destroyed the patient’s bone marrow, the reinfusion of those stem cells help regenerate the patient's bone marrow function, and facilitate a rapid recovery from the process.

(17:25): During the second week of admission, it is common to see some side effects and acute problems arise from the conditioning regimen. First and foremost, the patient will have extremely low blood counts, including very low white blood cells, platelets, and red blood cells. Many patients will need blood or platelet transfusions. There is a high risk of infection – due to their lowered white blood cell counts – and some patients develop fevers and require antibiotics.

(17:59): We also may see inflammation and damage to the oral mucosa – the lining that covers the inside of the mouth. This damage and inflammation can spread to the bowels and cause diarrhea and other discomforts as well. However, this is far less common than compared to allogeneic transplants.

(18:15): Typically, around day 10 we start to see a recovery of the blood counts, and sometime around days 12 to 15, patients are usually well enough to be discharged from the hospital. In my experience, it takes an average of 12 days from the time we infuse the stem cells to the time the patient is discharged.  

(18:39): There is a long list of autoimmune diseases that can be treated with autologous transplantation, and I have organized a handful of them into three groups – neurological, gastroenterological, and rheumatological.

(18:54): Within these neurological diseases, by far the most common one is multiple sclerosis. Other diseases include myasthenia gravis, stiff person syndrome, and neuromyelitis optica.

(19:13): For rheumatological conditions, the disease that we most commonly transplant is scleroderma, but transplant has been used for patients with lupus, inflammatory myositis, rheumatoid arthritis, Behcet's disease, vasculitis, and others.

(19:33): Within gastroenterological autoimmune diseases, typically we treat Crohn's disease.

(19:38): I'm going to dedicate the rest of my time to multiple sclerosis, Crohn's disease and scleroderma.

(19:49): Multiple sclerosis (MS) is the most common cause of neurological disability in young adults, with a median age of diagnosis at 30 years. It is three times more common in women, and can be very difficult, as these young women are in the most productive time of their lives, and are then being affected by a devastating disease. There is an immune attack of the myelin, which is the protective cover around the axons of neurons – shown in yellow. This causes damage and breakdown of the myelin. Axons transmit impulses from one neuron to another, but due to the damage of the myelin, the axon is exposed and eventually, the neuron is damaged and dies. In the picture, you can see the typical white plaques in the brain that can be seen on a scan.

(20:50): This causes progressive neurological disability and loss of function. The disease can become debilitating, and drastically affects patients’ lives and independence. These patients can lose their ability to walk, and even become blind or lose their ability to talk. They end up requiring a lot of care, and become confined to their homes.  

(21:16): Multiple sclerosis is the most common autoimmune disease that is treated with an autologous transplant. We have been utilizing transplants for MS for 20 to 25 years, and hundreds – probably now thousands – of patients have been treated.

(21:44): There has been one prospective comparative trial, in which treatment with a transplant was compared with the best available therapy. Based on all of the data that has been collected over the years, the American Society for Transplantation of Cellular Therapy (ASTCT) endorsed autologous transplants as “an efficacious and safe treatment for active relapsing forms of multiple sclerosis to prevent clinical relapse, MRI detectable activity, and worsening disability.” So here, they are highlighting various forms of relapse. The relapsing forms of MS are the earliest stage of the disease, typically occurring within the first four to five years of the disease.

(22:36): This graphic shows a prospective comparative clinical trial – called the MIST trial – illustrating the proportion of patients who had disease progression over 60 months. It indicates that patients who got a transplant only saw disease progression in 10% of their patients. The group who didn't get a transplant, shows that disease progression occurred in close to 80% of the patients. So, the efficacy of an auto transplant is very clear.

(23:37): This next graphic shows the proportion of patients with no evidence of disease activity (NEDA) by clinical assessment and by MRI imaging. This lists a significant number of therapies currently on the market for MS treatment. This graphic shows that only 40% - 50% of patients remained progression free, compared to the patients who underwent transplantation, where it fluctuated between 70% - 95% remaining progression free.  

(24:39): Looking at the data, it is clear that autologous transplantation is effective in a majority of patients with multiple sclerosis, and is more effective than the current standard disease-modifying therapies. It's most useful in the early stages of the disease – particularly during the relapse and remitting inflammatory phase, which usually is the first four or five years before the patient has accumulated neurological damage or progressed to the late degenerative phase. Transplantation induces remission that may last decades, and it’s a one-time treatment. There is still a risk of relapse over time, which has been as high as 20%.

(25:27): Now, let’s discuss scleroderma.  

(25:32): Scleroderma – also called systemic sclerosis – is a rare rheumatologic disorder characterized by vascular damage and extensive organ fibrosis and injury. This fibrosis is the core of the disease, and the deposition of scar tissue in multiple organs of the body that leads to progressive organ injury.

(25:58): These pictures show various ways one can be affected by this disease. While it’s difficult to see in this picture, this patient’s skin has become extremely thickened – you can see it looks bright and shiny – and the result is that the patient loses mobility of their hands and joints, and are unable to close their hands or grab or manipulate objects. That rigidity of the skin progresses all over their arms, legs, and torso, and becomes extremely incapacitating.

(26:39): This next picture shows interstitial lung disease, where you can see progressive deposition of scar tissue in       the lungs. And the final picture shows what we call Raynaud's phenomenon, which occurs when the small arteries in the fingers close, and blood flow cannot reach the fingers. This is why the fingers are white.

(26:59): The hallmark issue of scleroderma is progressing fibrosis that affects several organs, but generally patients die from lung and heart fibrosis. There is also renal dysfunction, gastrointestinal involvement with malabsorption, and malnutrition. Literally, the patient is trapped in his own body; there is all this scar tissue in all the organs of the body. And the mortality rate – even with the best therapies – is as high as 30% by 10 years.

(27:37): Three prospective comparative studies - SCOT, ASTIS, and ASSIST – proved that autologous transplantation is superior to the best available therapy. And the American Society for Bone Marrow Transplantation endorses autologous transplant as the standard of care – it should be used in every patient with scleroderma that fails standard treatment. If one or two lines of therapy are not working, the patient must have a transplant to prevent the progression of the disease.  

(28:21): Autologous transplant stops the disease in its tracks, allows certain organs to heal, improves quality of life, and induces long lasting remissions.

(28:34): These are graphs of some of the prospective comparative trials. In the ASTIS trials, the overall survival during a 10-year follow-up increased. Transplanting patients with scleroderma decreased mortality.

(28:48): Another trial is the SCOT trial, which was a multi-center trial in America. It showed transplantation was far superior than cyclophosphamide in overall survival and event-free survival.

(29:22): It is clear, patients with scleroderma who receive an autologous transplant, will have increased survival rates, and many more will have long lasting remissions and improvements in quality of life. Literally, you can see patients who were wheelchair bound prior to transplant, getting back to a normal life, and even back to work post-transplant.  

(29:51): Finally, let’s discuss auto-transplants for patients with Crohn's disease. Crohn's disease is a very severe autoimmune inflammatory disease of the gastrointestinal tract. It most commonly affects the colon and the ileum, which is the last portion of the small bowel. It causes extensive ulceration throughout the colon and small bowels. This leads to diarrhea, malabsorption, fevers, weight loss, and poor quality of life.

(30:25): This is a picture of a normal lumen of the bowels, which can be compared to the picture showing Crohn's disease, which has inflammation of the bowel, and narrowing of the lumen. Not only that, but this is further complicated by the formation of abscesses, where the bowel perforates, abscesses form and collections of pus arise. Oftentimes, there are also fistulas – which are the formation of small tunnels that go across the tissues all the way to the skin. These patients end up requiring frequent surgeries to resect affected segments of the bowel, and progressively lose multiple bowel segments.

(31:21): I didn't include graphics showing the results of some clinical trials, but there have been several trials studying transplants to help with Crohn's disease, and results indicated transplants can induce long-lasting remissions – free of therapy – in a large proportion of patients.  

(31:36): However, the risk of relapse in Crohn's disease is much higher than in patients with scleroderma or multiple sclerosis. So, by five years after the transplant, somewhere around three-quarters of the patients will have relapsed. However, patients who relapse respond much better to many therapies that they have failed in the past. So, the disease behaves in a different, much more benign way, after the transplant. And patients still experience a better quality of life and better control of the disease.

(32:20): So, can an autologous transplant cure autoimmune disease? It is not entirely clear yet. Many patients have remained in remission, and free from disease and need for therapies for 10, 15, even up to 20 years. Are they cured? We really don't know. But remaining in remission and not requiring any therapies for 15 to 20 years is significant.

(32:48): There are a few factors that help determine if someone is a good candidate for a transplant for an autoimmune disease. Unfortunately, most patients are sent to us for a transplant as a last resort, after every other treatment has failed. Many patients have accumulated significant amounts of irreversible damage, and many patients are malnourished, very weak, and debilitated. We don’t want to see that.

(33:15): We want to see patients in the first five years of the disease, before the disease has caused extensive damage. And even sooner in patients with scleroderma, because many available therapies are less successful and fail in most patients.

(33:35): The patient should be free of any other major medical problems. We cannot transplant a patient with severe heart or lung disease. We have to be very careful, and ensure the transplant will be safe. Also, we recommend early consultation with a transplant physician who has experience in autoimmune disease, to establish if the patient is a good candidate.

(34:05): There must be a lot of close collaboration with a multidisciplinary team – such as rheumatologists, neurologists, and gastroenterologists – to ensure the patient is a good candidate for a transplant.  

(34:41): Short-term side effects of autologous transplant for autoimmune disease are manageable, and often resolve during the patients’ time in the hospital. Blood counts will be very low, increasing risk for infection. Some patients develop fevers, and some need antibiotics. There is some risk of organ injuries, and sometimes we see instances of pulmonary edema, or inflammation of the small intestine. We address these side effects during the transplant and hospital stay.

(35:16): After discharge, patients may still be weak, but recovery is relatively quick. The patient remains immunocompromised for at least three months, as the immune system has been reset and needs time to regenerate. A few patients may develop a second autoimmune disorder. This has been noted in some of the publications, but is very rare.

(35:49): There are some long-term effects as well – certainly the most feared is the recurrence of the autoimmune disease. There is a very small risk of secondary malignancies caused by treatment with chemotherapy. However, this is very, very rare and is more of a risk when transplants are done to treat blood cancers.

(36:13): Patients who have had a transplant often experience a slow recovery. They may need physical therapy, rehabilitation and occupational therapy. If they have any comorbidities prior to transplantation, this can add onto recovery time as well. But, with proper support, patients recover and are able to get back to normal life.

(36:46): Summary. In summary, autologous transplantation induces long-term remissions in most patients with autoimmune disease. The proportion and the duration of those remissions depends on the primary disease and the number of previous therapies, but we see in most patients a major improvement in quality of life.  

(37:22): Many factors are taken into account to ensure a transplant will be safe, and ideally transplantation occurs in the first five years of the autoimmune disease for optimal effectiveness.

(37:37): And, as always, it’s important to maintain close collaboration between the transplant specialist and the referring physician. Thank you very much to all of you for listening.

Questions and Answers:

(37:58): [Thom Stewart]: Thank you, Dr. Ayala, for the excellent presentation.  

(38:16): "My husband is 155 days post-transplant for Wiskott-Aldrich. What, if any, experience or knowledge do you have with Wiskott-Aldrich? And whether or not it is cured with a transplant in an adult?"

(38:35): [Dr. Ernesto Ayala]:  Wiskott-Aldrich is an extremely rare immune disorder. I suspect he probably got a donor transplant – an allogeneic transplant. When the patient receives a donor transplant, he will acquire the new immune function that comes with the marrow cells from the donor. That will replace the patient’s old immune system in hopes of curing the disease, but this is a very unique and rare entity.

(39:24): [Thom Stewart]: "I had an autologous stem cell transplant for multiple myeloma a year ago. I also had alopecia areata prior to my cancer diagnosis. Is it possible that I won't see a recurrence of the alopecia since the stem cell transplant that I had last May?"

(39:49): [Dr. Ernesto Ayala]:  Yes, one of the ways we learned that autologous transplants work for autoimmune diseases is because patients who were having autologous transplants for blood cancers, also noted low remissions of the autoimmune disease. I don't know specific data on autologous transplants for alopecia areata, but I can tell you that if the transplant was successful, there is a good chance that the alopecia will remain in remission for a long time.

(40:37): [Thom Stewart]: "Do you have any comments on using fecal microbiota transplantation to treat autoimmune diseases?"  

(41:08): [Dr. Ernesto Ayala]: Fecal microbiota has been tried for gastrointestinal disorders like Crohn's disease, as well as in some other autoimmune diseases. It's based on the idea that by providing normal microbiota, we will re-establish or create an equilibrium with the bacteria that is inside us. The data is still developing and is limited, and this has not been widely used for autoimmune disease. I would say that the jury is still out.

(42:06): [Thom Stewart]: “Recent studies have shown that butyrate production and consumption are imbalanced in rheumatoid arthritis, and that the immune status and joint symptoms of RA model rats can be improved by dietary butyrate supplementation. Is long-term supplementation of butyrate recommended for the improvement of autoimmune disease?"

(42:33): [Dr. Ernesto Ayala]:  No, it is not included in any standard treatment. There may be some data, but you probably need to ask a rheumatologist if that type of diet works. As a stem cell transplant doctor, I probably would not be the person to answer that question.

(42:53): [Thom Stewart]: "How is it determined whether an autoimmune patient is a good candidate for transplantation?"

(43:07): [Dr. Ernesto Ayala]: First of all, we don't want the patient to have accumulated a lot of damage, or lost a lot of function because of the autoimmune disease. So, we try to ensure we see patients in the early stages of the disease.

(43:41):  Then, we perform the pre-transplantation workup and assessment to ensure transplantation is safe for this patient. We want to know what infections our patient has been exposed to. And, as I explained, we do extensive testing of the heart, lungs, kidneys, and liver to ensure the organs are functioning sufficiently for the transplant to proceed.  

(44:32): [Thom Stewart]: "Are transplant outcomes different for autoimmune patients compared to cancer diagnosis?"

(44:43): [Dr. Ernesto Ayala]:  They're different because we're treating two completely different diseases. I do many transplants for blood cancers such as lymphoma and myeloma, with the goal of inducing long-lasting remissions to keep them cancer free.

(45:14):  But with an autoimmune disease, we're trying to stop the progression of organ damage. We want to make sure that the lungs, heart, and kidneys are no longer damaged by the autoimmune disease, and reestablish quality of life and functionality. So, the goals are different, but yes, autologous transplantation is effective either way.

(45:52): [Thom Stewart]: "What are the chances that my lupus will go into long-term remission after the transplant?"

(46:25): [Dr. Ernesto Ayala]: While I didn't present data on lupus, there are many publications using autologous transplantation for lupus. When you look at these trials collectively, somewhere around 60% to 70% of patients with lupus can expect a long-term remission from the disease after an autologous transplant.

(46:56):  There have also been many new antibodies and disease modifiers created for those with lupus, so we don't see many patients with lupus referred to us. And now we have CAR T-cell therapy, which is a new type of immunotherapy now being used for patients with lupus with excellent results. So yes, autologous transplantation is effective in patients with lupus.

(47:37): [Thom Stewart]:"I have AML and will have a stem cell transplant this summer. I also have rheumatoid arthritis. Will my RA be gone after my stem cell transplant?"

(47:56): [Dr. Ernesto Ayala]: I think there is a very good chance your RA will disappear. And the reason is very simple: your immune system that is currently causing the AML will be replaced by a new, healthy immune system from the donor.

(48:23):  Now, you could still have some residual joint pain or some discomfort because of the damage the RA has already done. So that may persist, but the inflammation and the presence of the disease itself should disappear.

(48:55): [Thom Stewart]: "I have Crohn's disease. When should I consider a transplant?"

(49:06): [Dr. Ernesto Ayala]:  This is a very good question, and one of the most important questions to me. The patients that we have seen for transplantation with Crohn's disease, have all already been thru 10 to 15 years of disease. When they come to us, the disease has been relapsing for years, so many of them have lost their colon and some may have an open stoma outside the body because they lost extensive portions of the bowel.

(49:56):  So as I said, the best results of autologous transplantation are when it is used early. So in patients with Crohn's disease that have received the best available therapy – including at least two disease-modifying antibiotics – and experience a relapse, they should be referred for an autologous transplantation.

(50:29): [Thom Stewart]: Closing. Thank you. And on behalf of BMT InfoNet and our partners, I would like to thank Dr. Ayala for an excellent talk, and an exciting look at the future of transplant and autoimmune diseases. And thank you, the audience, for your excellent questions.

(51:00): [Dr. Ernesto Ayala]:  Thank you all for your attention.

(51:04): [Thom Stewart]:  Please contact BMT InfoNet if we can help you in any way. We hope you enjoy the rest of the symposium. Thank you.