How to treat a disease that had never been diagnosed anywhere in the world? The Pediatric Rheumatology Department of The Second Affiliated Hospital of Wenzhou Medical University had received a special young patient with such a disease.

Among the vast number of living beings, there is a group who experience a terrifying "battle" within their tiny bodies. Due to the abnormal immune system, they have to endure severe inflammatory reactions, including arthritis, recurrent fevers, rashes, and even ulcers, which are known as autoinflammatory diseases.

Eleven-year-old Lily (pseudonym) started experiencing swelling and pain in her lower limb joints at the age of one. The hospital she visited then diagnosed the disease as osteomyelitis and carried out surgery for her. They sought medical help everywhere and visited multiple hospitals. However, neither surgeries nor pharmaceutical treatment helped. Lily had been tormented by unbearable joint pain for 11 years. As time went on, walking became increasingly challenging for Lily, let alone physical exercises. After the age of 11, she was only 122 cm in stature, equivalent to that of a 7-year-old girl, causing her to feel inferior and voiceless amongst her classmates.

Her wrists cannot bend properly before treatment.

Her knees exhibit outward deviation and limited extension before treatment.

In August 2020, Chief Physician Zheng Wenjie of the Pediatric Rheumatology Department received Lily at her outpatient clinic at the Second Affiliated Hospital of WMU. The fact that Lily had an early onset of the disease with a long medical history and multiple joint involvement immediately rang alarm bells. Dr. Zheng admitted her to the hospital for further examination. The comprehensive examination revealed that Lily's disease differed from the common juvenile idiopathic arthritis, as the lesions were not only in the joints but had also extended into the bone marrow and affected multiple parts of her body, including the radius, ulna, tibia, fibula, femur, and sacroiliac joints.

Even walking and getting up are very difficult for her.

She is significantly shorter in height compared to her peers before treatment and feels inferior.

Dr. Zheng facilitated a multidisciplinary consultation for Lily's arthritis. An MDT team consisting of Chief Surgeon Zhang Jingdong from the Pediatric Orthopedic Department, Chief Physician Yang Yan from the Ultrasound Imaging Department, Chief Physician Cai Zhisheng from the Radiology Imaging Department, Chief Physician Chen Xiang from the Pediatric Rehabilitation Department, and Attending Physician Ye Xiaohua, conducted a joint outpatient consultation for Lily. A rare diagnosis of chronic recurrent multifocal osteomyelitis (CRMO) was made. Despite some improvement in joint swelling and pain, the treatment failed to improve the bone marrow edema or lower Lily's inflammatory markers to normal levels. Dr. Zheng suspected that Lily might have a rare autoinflammatory disease. However, as the results of the whole-exome sequencing came back negative, the diagnosis and treatment seemed to hit a brick wall.

Dr. Zheng then reached out to Professor Zhou Qing from the Life Sciences Institute at Zhejiang University. Prof. Zhou is an expert in autoinflammatory diseases and the discoverer of multiple such disorders. Prof. Zhou and her research team conducted another thorough analysis of Lily's genetic data and surprisingly discovered a de novo K131E mutation in Lily's IL-1R1 gene. This mutation hindered the binding of the IL-1 receptor to its antagonist IL-1Ra, leading to systemic hyperinflammation in the child. Such a disease caused by the mutation of the IL1R1 gene had not been reported worldwide before. Was it the cause of the systemic inflammation in Lily? After more than a year of series of molecular biology, cytobiology and animal experiments, the pathogenicity of IL-1R1 K131E was confirmed, thus uncovering the true culprit behind Lily's high levels of inflammatory cytokines.

In light of the biological characteristics of Lily's gene mutation, targeted biological drugs were deemed the most suitable option. However, the selection of medication for a rare disease that had never been reported before was a serious clinical challenge. With the support of the hospital leadership, after organizing numerous internal and external expert discussions and obtaining approval from the medical ethics committee, Dr. Zheng administered the selective IL-1β inhibitor, canakinumab, to Lily. Surprisingly, after more than a year of treatment, Lily's joint swelling and pain significantly improved, her inflammatory markers returned to normal levels, and most importantly, the bone marrow edema noticeably subsided.

After consulting relevant information, it has been found that this is the first reported case of an autoinflammatory disease caused by an IL1R1 gene mutation worldwide. Prof. Zhou and Dr. Zheng named this new type of autoinflammatory disease Loss of IL-1R1 Sensitivity to IL-1Ra (LIRSA). The research result was published on June 13, 2023, in the prestigious immunology journal "Immunity", showing the contribution of Chinese healthcare professionals to conquering immune-related diseases for all of humanity.

Lily is now only slightly shorter than her mother and feels much more confident.

Eleven-year-old Lily, who used to walk unsteadily when she first came to our clinic, can now run and jump rope normally. Not only has her height reached 1.42 meters, but her personality has also become much more cheerful. The doctor's diligent exploration of medical skills and the precise medical concept of "not leaving anyone behind" have brought back a smile to this girl with a rare disease.

Autoinflammatory diseases (AIDs) are a group of rheumatic immune disorders characterized by systemic and organ-specific inflammation, often with genetic heterogeneity resulting from innate immune pathway dysregulation. To explain further, one can draw an analogy between inflammation in the body and fire. In these diseases, the fire within the body continues to burn intensely due to spontaneous activation of pro-inflammatory pathways, while the lack of firefighters (deficient anti-inflammatory pathways) fails to control the fire.   This results in recurrent or periodic fever, rash, serositis, arthritis, and even organ damage involving vision, hearing, liver, and kidney function. Since the first diagnosed case of NLRP3-related AIDs in our pediatric rheumatology department, we have been closely monitoring the progress in this field. In recent years, we have successfully diagnosed and treated over a hundred cases of multi-gene AIDs such as PFAPA syndrome, as well as more than ten cases of extremely rare single-gene AIDs in the world including PAMI syndrome, haploinsufficiency of A20 (HA20), and crack-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. Dr. Zheng Wenjie also participated in the development of the Exerts Consensus on Diagnosis and Treatment of Autoinflammatory Diseases in Children 2022.

Although AIDs are rare, once diagnosed, most cases can be treated with targeted drugs specific to the inflammatory pathways involved. Early diagnosis and treatment can minimize organ damage and greatly improve a child's quality of life. Lily's case, as the world's first reported case of a new autoinflammatory disease caused by IL-1R1 mutation (Loss of IL-1R1 Sensitivity to IL-1Ra, LIRSA), will be included in the "Online Mendelian Inheritance in Man" (OMIM) database which provides up-to-date information on human genes and genetic disorders worldwide.

Expert introduction:

Dr. Zheng Wenjie is the Deputy Director (in charge) of Pediatric Rheumatology Department, member of the Rheumatology Group of the Pediatric Branch of the Chinese Medical Association, member of the Pediatric Rheumatology and Immunology Committee of the Chinese Medical Doctor Association, Deputy Head of the Rheumatology Group of the Pediatric Branch of the Provincial Medical Association, and visiting scholar at the Rheumatology and Immunology Department of the Cincinnati Children's Hospital Medical Center in the United States. She has been awarded the Provincial Science and Technology Progress Award and the Municipal Science and Technology Progress Award. Her main research areas are the biological treatment for idiopathic juvenile arthritis and genetic molecular mechanisms of AIDs.

She specializes in the diagnosis and treatment of pediatric arthritis, streptococcal infections, lupus erythematosus, dermatomyositis, Sjogren's syndrome, allergic purpura, hyperuricemia and gout, scleroderma, Behcet's disease, recurrent fever of unknown origin, and recurrent oral ulcers.

Outpatient hours: Monday afternoon, Friday morning, Sunday afternoon (special clinic).