The study of rare diseases sometimes depends on major international collaborations to obtain a more complete vision of the best therapeutic approach to a clinical condition that affects a small number of patients. This was the spirit that guided the work of a team of 83 researchers from 38 medical centers in 18 countries, including Brazil. The team of specialists contrasted the results of two approaches used to treat IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome, an unusual and serious autoimmune disease that only affects male newborns. Because of a genetic defect, the defense cells in these children mount an uncontrolled attack on various organs in their own bodies.
The first approach, known as hematopoietic stem cell transplant (using cells from the bone marrow or umbilical cord), attempts to provide the child with a new immune system containing healthy cells that do not manifest the disease (or at least express it to a lesser degree). The second, which is based on the use of immunosuppressive drugs, attempts to reduce the activity of the body’s defense cells, which in the case of IPEX syndrome turn against the body rather than protecting from external threats. Based on 96 cases treated from 2000 to 2016 in the countries participating in the study, the team found that the success rate of the two therapies was similar, although slightly higher for the transplants. The treatments improved quality of life in approximately two-thirds of the patients, according to an article published in March 2018 in the Journal of Allergy and Clinical Immunology.
However, the profile of patients who benefited the most from the adoption of each strategy differed. Retrospective analysis of the cases (58 treated with stem cells and 34 with immunosuppressive drugs) found that transplantation was the best long-term strategy for newborn infants or children whose organs had not yet been damaged by IPEX syndrome. “Transplantation is much more expensive than immunosuppressant therapy. It can cost from R$200,000 to R$500,000 and requires two to four months of hospitalization,” says pediatrician Juliana Fernandes of the Children’s Institute at the University of São Paulo School of Medicine’s Hospital das Clínicas (FM-USP), who participated in the study. “But when it works, after two years the patients no longer need to take medications or be hospitalized. And those who only have immunosuppressant treatment will probably have to be hospitalized again.”
As a result, treatment with medications, which leaves the patient more vulnerable to infections, is only advised in patients who already have organ damage (in these cases, transplantation produced poor results, according to the study) or as an alternative to halt the progression of the disease before transplantation. The University of São Paulo participated in the study, with five cases of children with IPEX syndrome treated since 2008. Three of the five children received transplants of stem cells from their parents’ bone marrow or extracted from the umbilical cord. The transplants were paid for by the Brazilian Unified Health System (SUS).
Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
Mutations in the forkhead box P3 (FOXP3) gene on the X chromosome, which impairs normal functioning of a specific group of blood cells, regulatory T lymphocytes. As a result, the defender cells begin to attack other cells and organs
Incidence in the population
Unknown. Affects only male newborns
Type 1 diabetes, chronic diarrhea, lower levels of red blood cells, antibodies, and platelets; inflammation and damage to the liver, kidneys, joints, and thyroid
Immunosuppressants or hematopoietic stem cell transplant (from bone marrow or the umbilical cord), with an efficacy of 70%
Sometimes the treatment must be repeated before it is successful. “In 2009, a 2-year-old boy weighing 6 kilograms had diabetes, hepatitis, anemia, and kidney damage because of IPEX,” says Fernandes. The first transplant did not produce the desired results, but a second one performed six months later was effective. Of the boy’s initial problems, only diabetes remained, and the boy is now 13 years old. His twin brother was born with the same disease although affected less severely; nevertheless, he died from a severe infection before undergoing the procedure. The boy who survived has another brother, who is 6 years old and was also born with IPEX syndrome. He underwent two bone marrow transplants, the second of which was successful. They are doing well and are followed by teams from USP at annual consultations.
Because it is rare, complex, and fatal, IPEX syndrome has always led to uncertainty among physicians. “There are no general guidelines, and treatment depends on the experience at each medical center,” says Italian pediatrician Federica Barzaghi of San Raffaele Hospital in Milan, who led the international study. “An assessment of the results and a comparison between the two types of treatment, with a large case sample, had never been done.” The disease results from mutations in a gene on the X chromosome, forkhead box P3 (FOXP3), which impair normal functioning of a specific group of blood cells, regulatory T cells (a type of lymphocyte).
When these cells do not work correctly, they create an imbalance in the body’s defense system and other types of lymphocytes begin to attack the body’s own cells, a typical trait of autoimmune diseases. “Intensive study of IPEX enriches our knowledge about the body’s defense system and other autoimmune diseases, because it allows us to see how the regulatory T cells are essential to maintaining cellular tolerance and not attacking other cells in one’s own body,” explains pediatrician Magda Carneiro Sampaio, a professor at FM-USP and director of the Children’s Institute. According to a 2016 article published in Nature Reviews Cardiology, regulatory T cell dysfunction may encourage cardiovascular diseases such as atherosclerosis, hypertension, abdominal aneurysm of the aorta, pulmonary hypertension, and heart attack.
In IPEX, which brings together several autoimmune disease symptoms, the failures of regulatory T cells caused the following impacts in the cases examined in the study, in order of frequency: type 1 diabetes resulting from pancreatic damage; chronic diarrhea; reduced numbers of red blood cells (leading to anemia), antibodies (leading to allergic reactions and red spots on the skin), and platelets (impairing the blood’s ability to clot); inflammation and damage to the liver, kidneys, joints, and thyroid; and hair loss. Another conclusion from the analysis of 96 cases was that the predominant symptoms of the syndrome occur regardless of the type of mutation in the gene that controls the maturation of regulatory T lymphocytes.
“The two treatments used today for IPEX still need to be improved, because each reaches a maximum efficiency of 70%,” says Carneiro-Sampaio. The collective work to analyze the syndrome also showed that a definitive cure can only be achieved by correcting the genetic flaw that causes the disease, according to Barzaghi: “We hope that gene therapy will soon be possible for the children with the most severe cases.”
BARZAGHI, F. et al. Long-term follow-up of Ipex syndrome patients after different therapeutic strategies: An international multicenter retrospective study. Journal of Allergy and Clinical Immunology. Vol. 141, no. 3, pp. 1036–49. Mar. 2018.
MENG, X. et al. Regulatory T cells in cardiovascular diseases. Nature Reviews Cardiology. Vol. 13, no. 3, pp. 167–79. Mar. 2016.