The lucky life of a rare disease patient
Health Times reporter Mao Yuanyuan
■In 2013, Lin Jian accidentally suffered a fracture, which did not heal for a long time, and the place where the tooth and alveolar bone came into contact was inflamed from time to time, and if it was not treated in time, a large hole of 2 cm would appear. Lin Jian realized that he might not be as simple as a "fracture", and he began a long journey to search for literature.
■"At that time, the only way to treat it was to take 'phosphate water' (phosphate preparation), and at the beginning, I could buy 'phosphate water' made by the hospital from the hospital, but after the hospital stopped selling this kind of in-hospital preparation, I had to make it myself!" Lin Jian said with a smile, "I bought chemical reagents from the laboratory and mixed them myself." ”
■In a literature review, Lin Jian saw that seven countries were conducting clinical trials for the treatment of hypophosphatemic rickets, and he sent emails one by one according to the above mailing address. He hoped that he would be able to participate in the treatment as well, even if there was only a little bit of hope. "Most labs either didn't respond or simply rejected it. ”
■"I didn't expect to be able to use innovative targeted drugs in China so soon, I was both excited and nervous, excited that I could finally inject this drug in China, and nervous that this drug was refrigerated at minus 2-8 degrees, and it needed to be injected within half an hour, for fear that I would not catch up if the step was slow!" Lin Jian said.
"I felt like a prawn, it took me five minutes to lie in bed, and I could hear the sound of 'popping' bones, which was painful. This is the self-report of a patient with a rare disease of hypophosphatemic rickets.
If the fracture does not heal for a long time, I know that I have a rare disease
Lin Jian (pseudonym), 32, suffers from X-linked hypophosphatemic rickets (XLH), a type of hypophosphatemic rickets that accounts for about 80% of hypophosphatemic rickets.
In 2013, Lin Jian accidentally suffered a fracture that did not heal for a long time, coupled with the inflammation of the contact between the tooth and the alveolar bone from time to time, Lin Jian realized that he might not be as simple as a fracture, and he began a long road of searching for literature.
"I've had root canal treatments on more than a dozen teeth so far, and I've had four or five oral cyst surgeries, and I have no problems with my teeth, but the contact between the teeth and the alveolar bone is often inflamed, resulting in erosion of the alveolar bone and cavities. Lin Jian told the Health Times reporter, "Later, I did root canal treatment for a toothache and quickly cured the inflammation and cyst." ”
The fracture was difficult to heal, so Lin Jian consulted a lot of literature and finally found the disease with the most similar symptoms to himself - hypophosphatemic rickets. Lin Jian found that the author of many of the literature was Professor Xia Weibo of the Department of Endocrinology of Peking Union Medical College Hospital, and Lin Jian immediately decided to go to the doctor in a wheelchair. "Professor Xia looked at my clinical performance, combined with biochemical tests - abnormal blood phosphorus and alkaline phosphatase indicators, and in 2015, I was diagnosed with X-linked hypophosphatemic rickets. ”
Professor Xia Weibo introduced that hypophosphatemic rickets is a group of rare diseases characterized by hypophosphatemia due to increased renal phosphorus excretion due to hereditary or acquired causes, which has been included in the first batch of rare diseases No. 51 rare disease. X-linked hypophosphatemic rickets is a type of hypophosphatemic rickets, which is caused by an excess of fibroblast growth factor 23 (FGF23) product due to PHEX gene mutations, which accounts for about 80% of hereditary hypophosphatemic rickets and has a high rate of disability and teratogenicity.
"Some children may not have clinical manifestations at birth, but by about 1 year of age, they will have difficulty walking, swaying gait, growth retardation, and slowly progress to skeletal deformities, causing bone pain. Xia Weibo introduced that some people will find abnormal manifestations in other parts, such as the mouth.
According to the "Survival Report of Hypophosphatemic Rickets Patients in China", the first survey report on the survival status of patients with hypophosphatemic rickets in China and the largest sample size in the world, patients with hypophosphatemic rickets are young at the age of first consultation, with an average age of 5.8 years old, but 72% of patients are not diagnosed after the first consultation, and some are even diagnosed after visiting 18 hospitals. 63.6% of patients experienced misdiagnosis, which is often confused with vitamin D deficiency rickets.
In fact, "the diagnosis of hypophosphatemic rickets is not difficult, through clinical manifestations, combined with biochemical tests, abnormal blood phosphorus and alkaline phosphatase indicators can be found, so as to make a preliminary diagnosis." Xia Weibo said.
Luo Xiaoping, head of the Department of Pediatrics at Tongji Medical College of Huazhong University of Science and Technology and one of the participants in the "Survival Report of Chinese Patients with Hypophosphatemic Rickets", said that the diagnosis of hypophosphatemic rickets is difficult mainly because clinicians know little about this rare disease.
The largest retrospective study on XLH in China conducted by Professor Xia Weibo's team found that the main clinical characteristics of Chinese patients with X-linked hypophosphatemic rickets were short stature, lower limb deformity, hypophosphatemia and elevated blood FGF23 levels. A total of 166 PHEX gene mutations were detected, which provided an important clinical basis and guidance for the clinical application of targeted therapy for XLH in Chinese patients with XLH.
For the treatment of hypophosphatemic rickets, you can only prepare your own phosphorus water and take it
In 2015, Lin Jian was diagnosed with X-linked hypophosphatemic rickets, and there is no drug that can treat this rare disease.
"At that time, the treatment was to take 'phosphate water' (phosphate preparation), and at first I was able to buy 'phosphate water' made by the hospital from the hospital, but when the hospital stopped selling this in-hospital preparation, I had to make it myself. Lin Jian said with a smile, "Buy chemical reagents from the laboratory, and then blend them yourself according to the proportion the doctor said." ”
"It's very unpleasant!" Lin Jian couldn't describe its taste, and could only express it in four words, "And I have to drink phosphorus water 5 times a day!"
Xia Weibo said that before there was no drug treatment, including 78% of patients still using a combination of phosphate preparation + active vitamin D, the symptomatic treatment regimen was still used, but 64% of patients with hypophosphatemic rickets were not satisfied with the treatment effect. On the one hand, phosphate preparations have an astringent taste and should be taken 4~6 times a day, and patient compliance is poor, especially for pediatric patients.
On the other hand, some patients are intolerant to phosphorus, which will cause gastrointestinal adverse reactions, and will also increase the risk of complications such as hypercalciuria, secondary hyperparathyroidism, and nephrocalcinosis. Even if the "phosphorus" treatment is adopted, the blood phosphorus level in the patient's body still does not reach the normal level, and the deformed bones cannot be corrected, and it is difficult to improve the problem of growth retardation in the patient.
"For me, the effect of 'phosphate' is really limited, in the years when I used phosphorus, sometimes I was on one crutch, sometimes on two crutches, sometimes in a wheelchair, sometimes in bed. Lin Jian said that when he was sick, he realized that there was such inconvenience in life, "but I also met a lot of enthusiastic people, where I couldn't walk in a wheelchair, they would carry me up, and the four of them carried me together, and I was really moved at that time." ”
The situation of good times and bad times has made Lin Jian's temper not very good, and he has also had a lot of conflicts with his parents, "Looking back now, because of this disease, so many family members and friends who care about me have become unhappy because of me, and I feel a little guilty, but I am also very helpless and difficult to express." ”
Writing to 7 national laboratories, I just wanted to be treated
Later, in a literature review, Lin Jian saw that there were seven countries underway clinical trials for the treatment of hypophosphatemic rickets, and he sent emails to the above mailing addresses one by one, hoping to participate in the treatment and receive treatment, even if there was only a little hope. "Most of the labs either didn't respond or refused outright, and at that time the U.S. was already going through the drug application process, saying that I could go to the U.S. for treatment, but because there was no U.S. health insurance and the cost was high, they gave up. ”
However, the next situation rekindled Lin Jian's hope for life.
In April 2018, the U.S. Food and Drug Administration approved the marketing of broxorumab injection (trade name: Linping ®) for the treatment of X-linked hypophosphatemia in children and adults 1 year of age and older. In June 2020, broxolumab injection was approved for a new indication in the United States for patients with tumor-induced osteomalacia 2 years of age and older. In September 2019, broxolumab injection was approved for marketing in Japan, and Lin Jian received his first injection in Japan in December 2020. "After two weeks, my bone pain was relieved and it became easier to walk. By the third and fourth treatments, I was able to get out of crutches. As the treatment progressed, it became more and more convenient for me to go upstairs, and later, when I went downstairs, I moved from one step to the other, and I could go downstairs with my feet alternately. ”
The epidemic disrupted Lin Jian's plans for treatment in Japan, and he had to return to China, but life gave him another surprise. On January 15, 2021, the NMPA approved the marketing of broxolumab injection (trade name: Linping ®) for the treatment of X-linked hypophosphatemia in adult and 1-year-old pediatric patients. In March, the indication of broxolumab injection was expanded for adults with neoplastic osteomalacia. Commercial listing in July 2021. On September 28, the first prescription in the country was issued, and Lin Jian became the first patient with X-linked hypophosphatemic rickets injected with broxorumab in China.
Talking about his feelings, Lin Jian said: "I am both excited and nervous, excited that I can finally inject this drug in China, and nervous that this medicine is refrigerated at -2 °C ~ 8 °C, and the injection needs to be completed within half an hour, for fear that I will not catch up if the step is slow!"
"Now I can walk and play badminton on my own, and the most important thing is that I can take care of myself. As a human being, my life is not only about healing, I have a job, I have friends, I have the right to live, and a more complete life will be happier and more fulfilling. Lin Jian told the Health Times reporter.