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The term 'rare disease' already suggests that there are difficulties in dealing with such a diagnosis. And it is a fact that there has been a lot of progress in terms of regulation, technologies, and treatments. However, the Awareness-raising about these diseases and the protocols of the health systems still need improvements to be able to offer a higher quality of life for an audience that does not seem to diminish.
To date, about 8 thousand rare diseases have been registered in the scientific literature, but it is estimated that every year at least 250 new diseases be discovered. In Brazil, the data also indicate that at least 6% of the population lives with a rare disease - which is equivalent to about 13 million Brazilians. When we expand to the world stage, the estimate of people with rare diseases reaches 5%, equivalent to approximately 300 million people.
In this sense, genetic editing technologies are great allies. “Prevention is the best treatment. The little foot test today tracks a hundred diseases, dozens of rare diseases, and some of them are treatable,” he says Ciro Martinho, geneticist and director of the clinic Chromosome Genomic Medicine.
It is estimated that around 70% of rare diseases begin to manifest in childhood, well into the first years of life. Therefore, the sooner the diagnosis is discovered, the faster it will be to find solutions that improve the quality of life of the individual with a rare disease.
On the other hand, 72% of rare diseases are associated with genetic origins and these are precisely those that are the most difficult to find treatment. Therefore, the best alternative in these cases is to resort to genetic counseling and in vitro fertilization.
The role of genetic counseling
The best form of prevention against a rare condition is through genetic counseling and in vitro fertilization. “When it is already known that an individual in the family has a gene mutation, it is through in vitro fertilization that we are able to carry out effective prevention, because that woman is already pregnant with a known healthy baby,” explains the geneticist.
To illustrate the issue, it is worth recalling genetics classes from school and returning to the concepts of allele genes and heredity developed by Gregor Mendel. In short, the letter “A” (Reason) in its capital form is used to represent dominant genes, and “a” (Azinho) lowercase designates recessive genes. Thus, the mother offers one letter and the father offers the other, making it possible to obtain the following combinations: Aa (azão azinho, called heterozygous), AA (azon-azão, termed homozygous dominant) and AA (azinho-azinho, which forms a recessive homozygote).
This methodology helps to stipulate phenotypic and genetic probabilities. If a person has blue eyes, for example, it means that they received two azinhos (aa) as a genetic inheritance.
“In rare diseases, the vast majority of them are recessive (aa), with one mutation originating in the mother and the other in the father. Taking into account spinal amyotrophy, for example, if the parents have the mutation but don't have the disease, because one has a normal gene and the other is altered, then they have a 25% chance of having a child with the disease. It is a very common disease in Brazil and today there is treatment, but it is the most expensive treatment in the Pharmaceutical Industry, an injection costs around 78 million dollars”, explains Martinho. In this sense, genetic counseling appears to be the best cost-benefit measure.
Even so, awareness is still not enough. This is because most people know that there are risks for couples who have some degree of kinship. However, “there is no couple with zero reproductive genetic risk,” Martinho explains.
In cases where couples not they share a degree of kinship and not they have genetic mutations or fetal malformation in their family history, yet there are 2 to 3% risk of fathering a baby with a genetic condition. This is because, for every 100 babies born, 2 or 3 have congenital malformation. In addition, 50% of these malformations are of unknown causes.
For this type of situation, prevention becomes more challenging, but not impossible. It is possible to trace the risks of this audience through the analysis of the 500 thousand most common genes in the world population, “we took those with the highest incidence in the world population and tracked between the two, to see if together there is any reproductive genetic risk of giving birth to a baby with one of these recessive or sex-related conditions,” says Ciro Martinalho.
The journey to diagnosis
“The challenge begins with the lack of information and recognition in this very important area, which are rare diseases, whether genetic or non-genetic,” he says Antoine Daher, president of Hunter House, Rare Diseases Association, Febrararas (Brazilian Federation of Rare Disease Associations) and co-founder of House of the Rare.
The specialist continues, explaining that “when we use the term 'genetics' it reminds us that most of these rare diseases are of genetic origin and are therefore treated by geneticists. In the country we have only about 300 geneticists, which is very little for such a large health access network in our country,” says Daher.
With the scarcity of genetic specialists, the result is a long saga until the diagnosis is obtained and reaches the point of thinking about treatments. “The doctors' lack of knowledge is very great and this causes the patient to be lost in the network until they actually arrive at the right place where they can make the diagnosis. Even when you arrive at the referral center, after a great saga, until you find someone who can understand the disease, it takes 1 to 5 years until he can be assisted by a specialist in the public system,” says the president of Casa Hunter.
The speed of the process does not advance much after reaching the ideal specialist. It is estimated that between taking the battery of necessary tests and scheduling a return, the patient may take another year to reach a diagnosis. Thus, it may take up to 10 years for the patient to obtain a concrete report.
In the Unified Health System (SUS), the average time to obtain a diagnosis of rare diseases is 5 years and 4 months. “We are talking about an average diagnosis of five years and four months, knowing that 30% of those with rare genetic disorders die before the age of 5. But they don't die at home playing, they die making their families spend a lot of money treating the consequences and without treating the causes”, reiterates Antoine Daher.
The solution for this scenario? Change the approach protocols with a different management plan, in addition to care models and diagnoses that are more appropriate for the situation. “We are currently spending a lot, serving less and with less quality,” Daher analyzes.
To apply solutions in the health system - both in the public and private spheres -, Hunter House works in partnership with Febrarara. The changes began two years ago, with the approval of Enlargement of the little foot test, which went on to detect more than 50 diseases.
Currently, the organization is also focusing on developing bills to guarantee the democratization of access to health in Brazil. One of the main ones is the “Antoine Daher Law” bill, which requires all health centers in the country, whether public or private, to treat patients suspected of having a rare disease within 60 days. “If this bill is approved this year, we are going to have a radical change in the infrastructure and approach to the diagnosis of these patients,” explains the expert.
The costs of rare diseases
In 2020, the Ministry of Health announced that R$ 1.3 billion was spent on lawsuits for drugs in 2019. Of that amount, 1.2 billion reais were directed to drugs against rare diseases.
In addition, a new study carried out by the IESS (Institute for Supplementary Health Studies) this year, indicates that there was an increase in hospitalizations of beneficiaries with rare diseases between the years 2021 and 2022.
The study identified that the number of hospitalizations for beneficiaries with rare diseases increased 20.4% in supplementary health between 2021 and 2022. Sickle cell disease was the record holder for hospitalizations in both years, registering 22,978 cases in 2021 and 31,081 in 2022. Statistically speaking, there was an increase of 35%.
It is estimated that 60 to 100,000 people have sickle cell disease in Brazil. Therefore, the expenses of health operators with this disease increased by 58%. Of 23.08 million reais in 2021 and 36.44 million in 2022.
“The regulation of the incorporation of new drugs plays a crucial role in preventing excessive costs both for the Unified Health System (SUS) and for private health, both with limited resources. Through regulation, it is possible to negotiate prices with pharmaceutical industries instead of paying the highest prices in the market to comply with court decisions. Effective regulation is essential for the sustainability of both the SUS and private health operators”, describe the IESS researchers in the report “Rare diseases: overview of hospitalization expenditures in health plans in Brazil (2021 and 2022)”.
The future of rare diseases in Brazil
For the future of those dealing with a rare disease, the best prospects are associated with the transformations that medicine has undergone, thanks to investments in research aimed at genetic diseases. It was with this focus that science was able to develop target therapies.
“They will certainly be a reality closer to the general population in the next 7 to 10 years. And this will not only be for rare genetic diseases, but for common diseases as well,” says Antoine Daher.
Still with regard to technologies, Ciro Martinho believes that “our biggest obstacle now is exactly that, we have already been able to sequence the entire human genome. However, while in the United States this test already reaches the consumer for around 500 dollars, here in Brazil this type of test still costs around 10 to 15 thousand reais and does not provide all the information we would like. So, in terms of exams, it's quite possible that we're close to exhausting the amount of test information. The problem is that we still haven't been able to interpret it the way I would like. This is one of the great challenges that will possibly be minimized through Artificial Intelligence, because it no longer uses three or five variables as a human brain, it can use hundreds, even thousands of variables at the same time”, concludes the geneticist.
Finally, Antoine Daher affirms that the pilot project “Hospital dos Rares” is already a success in Porto Alegre: the average diagnosis time dropped from 5 years and 4 months to 41 days. The idea of Casa dos Rares is to develop a wide ecosystem of rare diseases: “if everything works out, we will take the project to São Paulo and it will not only have a Casa dos Rares Hospital as well, but it will be a complete center, offering more hospitalizations and surgeries, distributed in an 18-story building. This will revolutionize the treatment and diagnostic model for patients with rare diseases,” Daher concludes.
