In 2017, a movie called "Miracle Boy" touched countless people and won several Oscar nominations the following year.
The protagonist of the story, Auggie, is a 10-year-old boy with Treacher Collins Syndrome (TCS), a rare disease with an incidence of about 1 in 50,000, and patients are often born with facial mutilations and facial deformities.
But augie, who is strong and kind by nature, has not been defeated by the disease, and he constantly influences and moves the people around him with a positive and optimistic attitude, becoming an incredible "miracle" in everyone's mind.
Image source: Douban
The word "rare" in rare diseases has made countless people ignore its existence, and the valuable thing about Auggie's story is to pull the eyes of the global audience back to these groups that should be valued.
Rare diseases are those with a very low incidence.
There are some differences in the criteria for defining rare diseases from country to country: in the United States, rare diseases are defined as diseases that affect less than 200,000 people; in the European Union, rare diseases are defined as diseases that affect less than 1/2,000 of the entire population; and in China, rare diseases are defined as diseases with a neonatal incidence of less than 1 in 10,000.
Although the number of patients affected by a single rare disease is limited, there are more than 7,000 different types of rare diseases in the world, bringing the total number of rare disease patients in the world to 350 million, and the number of people on the mainland is 20 million.
The last day of February may be unremarkable for us. But for people with rare diseases, they can only be seen, noticed and understood on this day of the year, because today is the International Day of Rare Diseases.
Image source: Wikipedia
I hope that rare diseases will be seen by more people.
What are the common rare diseases?
On May 22, 2018, the National Health Commission, the Ministry of Science and Technology and other five departments jointly released the first batch of national editions of the Rare Disease Catalogue, involving a total of 121 diseases. Although it accounts for only a small fraction of the more than 7,000 rare diseases recognized internationally, this is the first time that China has officially defined rare diseases, which is a breakthrough in the field of rare diseases in China.
Image source: The Paper
Through this catalogue, we will find many "rare diseases" that are becoming less and less rare.
1. Spinal muscular atrophy
According to the results of the 2018 China Rare Disease Survey Report, Spinal muscular atrophy has the largest number of cases of any rare disease.
Distribution of rare diseases in China
This is a type of disease that causes muscle weakness and muscle atrophy caused by degeneration of motor neurons in the anterior horn of the spinal cord. Due to the degeneration of motor nerves in the spinal cord, patients may experience symptoms such as motor abnormalities, muscle weakness and muscle atrophy, and in severe cases, death due to "strikes" of respiratory muscles.
Spinal muscular atrophy is generally caused by mutations in the motor neuron survival gene 1 (SMN1). Patients with spinal muscular atrophy are born with a lack of SMN1 gene, resulting in insufficient SMN protein in vivo, and SMN protein is one of the key regulators of neurons, which plays an important role in the release of neurotransmitters and the metabolism of neurons.
The disease now has targeted drugs that can increase the copy of the SMN2 gene in the patient's body, although SMN2 is only responsible for synthesizing about 10% to 15% of the SMN protein in the body, but it can greatly alleviate the symptoms of muscle atrophy.
2. Multiple sclerosis
There is also a lot of news about multiple sclerosis.
In 2018, Hellboy heroine Selma Blair revealed that she had incurable multiple Sclerosis (MS) and that her condition was worsening, sometimes wrestling, blurred memory, and the left side of the body did not listen to the call; in the gene editing baby incident, some scholars pointed out that the loss of the CCR5 gene may affect the survival rate of patients with multiple sclerosis.
Image credit: Nature
Multiple sclerosis is actually not sclerosis, but multiple nerve damage, which is an autoimmune disease characterized by the leukoplasmitis demyelinating lesions of the central nervous system, and the patient's immune system will be abnormal and frantically attack the myelin sheath.
The patient demyelinating lesion area shows macrophages
As the ability of the nervous system to transmit signals is disrupted, a range of physical and mental problems can occur, such as numbness, pain, visual impairment, movement abnormalities, and psychiatric symptoms such as depression, irritability, and grumpiness.
Unfortunately, the etiology and pathogenesis of multiple sclerosis have not yet been fully understood, and recent studies have put forward a variety of theories such as autoimmunity, viral infection, genetic predisposition, and environmental factors.
3. Hemophilia
Hemophilia is closely related to the body's coagulation mechanisms. Blood clotting is the process by which coagulation factors are activated in a certain order, eventually transforming fibrinogen into fibrin, in which coagulation factors play an essential role.
The coagulation process, image source: Wikipedia
Due to the innate lack of coagulation factors in patients with hemophilia, once trauma occurs, the blood will not stop flowing, and there will be a slight post-traumatic bleeding tendency throughout life, and severe patients will have "spontaneous" bleeding even without obvious trauma. Lack of coagulation factor VIII, called hemophilia A, lack of coagulation factor IX, called hemophilia B. Among them, the former is more common, accounting for more than 80% of all hemophilia.
Coagulation factor VIII, image source: Wikipedia
The traditional treatment for hemophilia is the injection of exogenous coagulation factors to achieve a sufficient degree of coagulation in the body. However, about 30% of patients with hemophilia A have resistance to factor VIII, and even if injected, it is useless.
In 2018, on December 4, the State Drug Administration approved a new drug, Emicizumab Injection, for the treatment of hemophilia A, which can glue coagulation factor IX and coagulation factor X together, which plays the role of coagulation factor VIII without causing a resistance reaction.
In addition to these, there are also Pompeii disease, frostbite, Gaucher disease, Huntington's disease, etc., these rare diseases have gradually become known to the public in recent years. But these are just the tip of the iceberg of more than 7,000 rare diseases, and human understanding of rare diseases is still extremely limited...
The dilemma of rare diseases
In 1657, william Harvey, a well-known English physician and anatomist, recognized the importance of studying rare diseases, arguing that "discovering the basic laws of nature by carefully studying rare diseases is the best way to advance the correct practice of medicine."
However, nearly 400 years later, less than 5% of rare diseases still have a cure, and rare diseases are a common problem facing doctors, scientists and patients.
1. Difficult to diagnose and treat
How difficult is it to diagnose a rare disease?
Taking multiple sclerosis as an example, according to the survey results of the "Multiple Sclerosis Patient Survival Report (2018)", nearly half of China's multiple sclerosis patients cannot be diagnosed immediately, and 38% of patients will be misdiagnosed as optic neuromyelitis, anxiety, vascular diseases and other diseases, which are strange reasons that lead to the diagnosis cycle of multiple sclerosis is greatly lengthened.
Image source: Survival Report for Multiple Sclerosis Patients (2018)
This is not a problem with multiple sclerosis, but also other rare diseases. Relevant data show that 59% of Patients with Gaucher Disease have been misdiagnosed, 70% of patients need to be diagnosed by multiple hospitals to be diagnosed; Pompeii patients have a misdiagnosis rate of up to 84.4%, and 75% of patients have to go through 3 or more hospitals to be diagnosed.
Fortunately, the problem of high misdiagnosis rate of rare diseases has been highly valued by the relevant departments.
In 2018, the National Health Commission, together with the Ministry of Science and Technology, the State Food and Drug Administration and other departments, formulated a special "Catalogue of Recommended Hospitals for Rare Diseases". The catalogue recommends hospitals with diagnostic and treatment capabilities for all 121 rare diseases.
In 2019, the first "Guidelines for the Diagnosis and Treatment of Rare Diseases" in China was released, which comprehensively elaborated on 121 rare diseases from the aspects of disease overview, etiology, epidemiology, clinical manifestations, auxiliary examination, diagnosis and differential diagnosis, and treatment methods.
In the face of more than 7,000 rare diseases, these measures, although a bit of a drop in the bucket, are also valuable progress. It is hoped that in the future, the problems of low level of diagnosis and treatment of rare diseases and lack of experience and ability in diagnosis and treatment can be effectively solved.
2. Difficult to develop
Due to the small number of patients affected by each rare disease, coupled with the complexity of research and development, commercial companies have little incentive to invest in the research and treatment development of these rare diseases, which is a dilemma for scientists.
However, due to policy changes, many countries have given corresponding preferential policies to pharmaceutical companies that develop rare disease drugs, and the development of rare disease drugs is no longer unprofitable.
For example, after the United States gives R&D companies a 7-year market exclusivity period and reduces taxes of up to 50% of clinical R&D expenses, the EU and Japan have a market exclusivity period of up to 10 years.
Stimulated by a series of policies, the research and development of rare disease drugs is naturally effective. In 1983, the Orphan Drug Act was introduced in the United States, and only 10 rare disease drugs were listed in the United States in the first 10 years before the bill, but after 1983, this number soared to 503, covering 731 indications (as of September 2018).
In China, there are also many policy dividends.
Since 2015, the Chinese government has issued a number of policy measures such as the Opinions on Reforming the Review and Approval System for Drugs and Medical Devices to encourage the introduction, research and development and production of drugs for rare diseases, and to accelerate the registration review and approval of drugs for rare diseases.
On February 11, 2019, the state decided to give value-added tax concessions to rare disease drugs, the first batch of 21 rare disease drugs and 4 APIs, with reference to anti-cancer drugs, the import link will be reduced by 3% VAT, and the domestic link can choose to calculate VAT according to the 3% simple method.
Image source: Health Times
Although the support of policies cannot fundamentally change the difficulty of drug research and development, mobilizing the enthusiasm of orphan drug manufacturers will make the entire industry gradually pay attention to this field. It is believed that more enterprises will participate in the research and development of rare disease drugs.
3. It is difficult to buy medicine
The difficulty of buying drugs is a problem in front of patients. On the one hand, there is no cure for this problem.
Taking drugs for the treatment of multiple sclerosis as an example, after the expiration of the patent in 2013, the Chinese market can no longer buy Libi, and only Betasolone can be used by patients, but in 2016, Betasolon also withdrew from the Chinese market. During that time, patients with conditions had to go to Hong Kong or abroad to buy drugs, and more patients could only risk necrosis of the femoral head and use immunosuppressants to survive...
Image source: Caixin
In order to solve this problem, a number of measures have been introduced in China to accelerate the introduction of rare disease drugs that have been listed overseas. The effect was immediate, and in 2018, Betasolone returned to the Chinese market, and another oral disease correction drug, Obatje (trifluramide tablets), was also listed in the same year.
But the problem of no cure is still worthy of attention. Of the 121 rare diseases included in the national "First Rare Disease Catalogue", 53 rare disease treatment drugs have been listed in China, and the remaining rare diseases have been eliminated from 47 that have not yet been treated, which means that there are still 21 rare diseases facing the dilemma of "no medicine in China".
Another aspect of this conundrum is the high price of drugs.
For costly new drug research and development, high prices are almost inevitable to recover costs. The base of rare disease patients is relatively small, and the price of single drugs is difficult to amortize through scale.
Take Meierzan, the only drug that treats the root cause of Pompeii disease, as an example, a bottle of 50 mg of the drug is priced at 5600 yuan, and a patient weighing 40 kg needs 16 bottles at a time, that is, 89600 yuan, once every 2 weeks, up to 2.1 million a year, and it is necessary to take drugs for life...
The high price of drugs is prohibitive, and patients with rare diseases without exception pin their hopes on medical insurance payments, but behind this is a larger practical problem - is it reasonable for hundreds of people to pay for one person's medical insurance?
And subject to various reasons, the result of this high-priced drug into medical insurance is often medical insurance to the doctor layer by layer of pressure - pressure to the end of the high-priced drug less or even not open, then go to the hospital to "grab drugs" may become the only choice for rare disease patients, obviously this is not the result that everyone is happy to see.
It is not difficult to see that we still have a long, long way to go to overcome the problem of rare diseases. For the government and even the whole society, this is a very difficult problem, how to deal with the interests and contradictions of doctors, pharmaceutical companies, and patients is a very test of wisdom.
In the future, it is feasible to explore a solution with the participation of multiple parties such as medical insurance, commercial insurance, social charity, and pharmaceutical company donations, and cooperate in multiple models, continue to increase support and investment in the research and development of orphan drugs, and suppress low costs and prices through market competition.
- References:
1. "Five departments jointly released the national version of the list of rare diseases, a total of 121 diseases", Sina.com, 2018-05-24
2. "Inventory of Those Increasingly Uncommon Diseases", Tadpole Staves, 2019-01-11
3. "20 million rare disease patients, waiting for drugs to come", Interface News, 2019-02-28
4. "200 yuan a needle of imported drugs sold domestically 700,000? Don't come up and scold the black heart of the pharmaceutical factory, it seems so layman", Lilac Garden, 2020-08-07
Image source network.
Edit: Ivan