Autoimmune diseases are a heterogeneous group of disorders in which the immune system mistakenly attacks self-antigens. The cause of their pathogenesis is multifactorial and involves genetic factors, environmental influences, and a deregulated immune system, which affects different organs and systems, leading to chronic inflammation, tissue damage, and a variety of disabling symptoms. Conventional treatments of autoimmune disease, whether immunosuppression, corticosteroids, or biologic therapies, are all aimed at dampening down the activity of the immune system. For many, but not all, patients with these severe or refractory diseases, the relief provided by conventional therapies is inadequate, while side effects are serious.
Interest in AHSCT has increased in recent years as a new treatment modality for severe autoimmune disorders. Also popularly known as autologous bone marrow transplantation, in this process, hematopoietic stem cells responsible for blood and immune cell production are harvested from a patient followed by an ablative treatment of high-dose chemotherapy or radiation that eradicates an existing immune system. Following this conditioning phase, the harvested stem cells are reinfused into the patient with the idea of "resetting" his immune system. The justification behind the whole procedure is that in destroying the malfunctioning immune cells and re-infusing the healthy stem cells, AHSCT would lead to long-term remission and ultimately change the course of the disease.
The current article reviews the potential treatment of AHSCT for three major autoimmune disorders: multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. We will review mechanisms, clinical evidence, challenges, and considerations associated with this new approach and discuss its implications for the future of autoimmunity management.
Multiple Sclerosis (MS)
Multiple sclerosis is a chronic autoimmune disorder 'nervous system' disorder that affects the central nervous system. Myelin is a protective covering surrounding the nerve fibers of the victim's body. The body's immune system wrongly directs an attack on the myelin protective cover, causing destruction. This disrupts communication between the central nervous system and other body parts, thus giving a variety of neurological symptoms that include muscle weakness, fatigue, problems of coordination and balance, difficulties with vision, and even cognitive impairments.
Essentially, MS can be divided into three different subtypes according to the course of the disease: relapsing-remitting MS, secondary progressive MS, and primary progressive MS. In relapsing-remitting MS, periods of symptom exacerbation (relapses) are followed by periods of remission, while in secondary progressive MS, symptoms continuously progress with some less or no remission periods.
Autologous BMT in MS:
AHSCT has currently been considered in highly active RRMS and other aggressive forms of multiple sclerosis as an alternative treatment when conventional treatments, especially DMTs, were not successful in discontinuing the progress of the disease. AHSCT in MS is justified for "resetting" the immune system with the intention of stopping the autoimmune attack on the CNS and halting further neurological damage.
Clinical trials and observational studies have established the fact that AHSCT can induce long-term remission in a significant proportion of patients with MS. In some, even stabilization or improvement in neurological functions was observed post transplantation. In one report, for instance, almost 70% of the patients with RRMS treated using AHSCT were found to have remained relapse-free without any indication of disease activity over a five-year follow-up period of time.
This generally consists of harvesting the haemopoietic progenitor cells from the patient's blood or bone marrow, conditioning the patient with high-dose chemotherapy or radiation to destroy the existing immune system, and then reinfusing the harvested stem cells into the patient, where they migrate to the bone marrow and start to reconstitute a new immune system. The expectation is that this new immune system will be "reset" and will no longer attack the CNS.
There are, however, some risks to AHSCT. During the conditioning regimen, the individual may experience significant side effects, such as infections, bleeding, and organ toxicity. In addition, there is the risk of treatment-related mortality, though it has been said that with advances in supportive care, this risk has reduced over the past years. The potential benefits of the procedure have to be carefully weighed against these risks, and patient selection is therefore very important.
Generally, AHSCT is contemplated for individuals who are at risk of significant disability due to highly active MS and have not responded to other treatments.
Issues and Barriers in MS:
AHSCT, being an option in MS, is still under experimental conditions and is mainly available through clinical trials or at specialized centers. Outcomes depend on factors such as the general health status of the patient, the disease's stage when treatment started, and the aggressiveness of the disease. Although the results of AHSCT in MS look promising for long-term benefit, it still requires further studies before it is finally out so that the durability of remission is assessed and patient profiles are established for whom this approach brings the greatest benefits.
Systemic Lupus Erythematosus (SLE)
Systemic Lupus Erythematosus is a complex autoimmune disease presenting the possibility of dysfunctions related to a number of organs, including skin, joints, kidneys, heart, lungs, and brain. SLE is a disease of flares—periods of disease activity that are accompanied by periods of remission. The reasons for SLE, though not clearly understood, are considered to include genetic, environmental, and hormonal factors that appear to trigger an abnormal immune response, causing diffuse inflammation with resultant tissue damage.
There can be fatigue, pain in the joints, different skin rashes, malfunctioning of kidneys, and even involvement of nervous system. Disease can run from very mild, unnoticed forms of the process to serious, threatening conditions and complications.
Autologous BMT in SLE:
AHSCT has been investigated in patients with severe and refractory disease not responding to conventional therapies. The goal of AHSCT is resetting the immune system in order to achieve long-term remission through elimination of autoreactive immune cells responsible for the disease.
Clinical studies and case reports have shown that AHSCT can lead to major improvements in disease activity and organ function in some SLE patients. In a study in Arthritis & Rheumatology, it found that a subset of patients with severe SLE treated with AHSCT achieved and maintained sustained remission; some patients even had a complete resolution of disease symptoms. In addition, there was a significant reduction in the need for ongoing immunosuppressive therapy in these patients.
The AHSCT procedure in SLE involves taking hematopoietic stem cells from a patient's blood or bone marrow and then carrying out a so-called conditioning regimen with the intention of ablation of an already existing immune system. Following the reinfusion of the harvested stem cells, the recipients' reconstituted immune system is thus expected to be tolerant to the body tissues—the immune system is not supposed to attack them anymore.
As with MS, the risks of AHSCT in SLE include infections, organ toxicity, and relapse. The procedure is usually considered a last resort, after other options have been exhausted, and careful patient selection is paramount to minimizing the risks while optimizing benefits.
Challenges and Issues in SLE:
Though AHSCT is a promising treatment for severe SLE, the treatment is an experimental one and generally reserved in the setting of life-threatening disease, or with severe organ involvement, not controlled by conventional therapies. Further studies with long-term follow-up are required to understand if remission is sustained by AHSCT and its influence on survival and quality of life in patients with SLE.
Rheumatoid Arthritis RA
Rheumatoid Arthritis is an autoimmune inflammatory chronic disease that involves first of all articulations, but can also include other organs like lungs, heart, and eyes. RA is characterized by persistent synovitis, systemic inflammation, and the presence of autoantibodies. Over time, the inflammatory process may result in damage to the joints and even lead to deformity and disability.
Although the precise cause of RA continues to be obscure, it is believed to be genetic predisposition and environmental influences, particularly smoking, eliciting a host immune response against joint tissues. Clinical disease typically manifests with joint pain, swelling, stiffness, and fatigue. Still, in its more aggressive form, RA may lead to the marked functional disability and adversely affect the quality of life.
Autologous BMT in RA:
AHSCT has been investigated as a treatment for patients who have severe, refractory RA and have failed all other conventional therapies, including DMARDs and biologic therapies. The main objective of AHSCT in RA is to reset the immune system by eradicating autoreactive immune cells responsible for driving the inflammatory process and then replacing them with healthy immune cells.
Clinical outcomes with AHSCT in RA have been varied. Some studies have demonstrated improvement of joint symptoms, reduction of disease activity, and increases of functional capacity after transplant. For example, it was reported in the Lancet that a proportion of the patients with RA achieved long-term remission with AHSCT and were able to reduce or discontinue immunosuppressive medications.
However, there has been evidence from other studies showing that some patients do not reach a durable remission, and a subsequent relapse occurs after the procedure. Additionally, the risks related to AHSCT have to be weighed against the potential benefits, particularly in a disease like RA, where other effective treatments are available.
Challenge and Considerations in RA:
Use of AHSCT in RA is still entirely experimental and is generally kept for very severe cases where other modalities of treatment have failed. This is a highly risky procedure, and the selection of patients must be done very carefully so as to not bring about complications. Additional research is required to clarify issues on the long-term efficacy of AHSCT in RA and to ascertain which patients are more likely to benefit from this approach.
Challenges and Considerations with Autologous BMT for Autoimmune Disorders
AHSCT is an evolving and highly promising approach to the treatment of serious autoimmune disorders, but it is not without challenges. It carries a significant risk of infection, organ toxicity, and treatment-related mortality. Also, a concern about the possibility of disease relapse, as recorded with most patients having aggressive or long-standing disease, is constantly present.
Patient selection is the major step to potentially balance the benefit of AHSCT with these risks. Patients demand a careful pretransplant evaluation before the procedure, with the view of their general health, the severity of the disease, and whether they are fit for the procedure. The conditioning regimen may be intolerable for a patient with comorbidities or organ dysfunction.
In most cases, long-term follow-up and monitoring are necessary for assessing durability of remission and also for managing the complications that might arise post-transplant. Some patients will need extended immunosuppressive therapy and/or supportive care for preventing relapses and the management of late effects from the transplant.
Conclusion
Sharp AHSCT is considered a very promising treatment option in cases of severe autoimmune diseases, such as MS, SLE, and RA, that do not respond to conventional therapies. It is considered a potential way to change the course of these troublesome diseases, since it resets one's immune system and may evoke long-term remission of the disease.
However, AHSCT still is the treatment of experimental trials and restrains its use in patients who have no other possible alternative treatment options. The major risks are that it presents; hence, careful selection of the patients and an active follow-up over long-term are important in order to maximize benefits and minimize complications. Further studies are needed about factors that influence the outcome of treating autoimmune diseases with AHSCT, in order to further amend the criteria for selection of patients, so that the use of this innovative treatment modality is effective and safe.
As further studies evolve over the coming years, AHSCT holds promise to be accepted and become more available as a modality of treatment for the most severe cases of autoimmune disorders with patients hoping for better outcomes and living a good quality of life.
