Introduction
Cold porphyrin-related periodic syndrome (CAPS)Is a very rare group of autoinflammatory diseases, includingFamilial cold autoinflammatory syndrome (FCAS)Muckle-Wells syndrome (MWS), chronic infant neurocutaneous joint syndrome (CINCA), in which chronic infant neurocutaneous joint syndrome is also known as neonatal multisystemic inflammatory syndrome (NOMID). These syndromes were originally described as different clinical entities, although they have many clinical similarities: patients often present with fever, urticaria-like rash (pseudo urticaria) and varying degrees of joint involvement.
The severity of these three diseases is gradually increasing: FCAS is the mildest, CINCA (NOMID) is the most critical, and MWS is in the middle.
These three diseases have been shown to be caused by the same genetic mutation at the molecular level.
Cause
CAPS is a hereditary disease. The possible pathogenic gene for these three diseases (FCAS, MWS, CINCA/NOMID) is CIAS1 (or NLRP3), which encodes a protein called cold porphyrin. This protein plays an important role in the body's inflammatory response. If the gene is destroyed, it will lead to hyperporphyrin hyperfunction (function gain) and increased inflammatory response. The enhancement of the inflammatory response ultimately causes the clinical symptoms of CAPS.
However, 30% of patients with CINCA/NOMID did not find mutations in the CIAS1 gene. Genetic mutations in patients with milder CAPS did not have a serious effect, and vice versa. Other genetic and environmental factors can also have an impact on the severity and symptoms of the disease.
symptom
The rash is the main symptom of these three diseases and is usually the first symptom. The rash appears as a migratory rash (similar to urticaria) and is usually not accompanied by itching. The severity of the rash varies from person to person and is related to the activity of the disease.
FCAS, formerly known as familial cold urticaria, is characterized by recurrent episodes of short-term fever, rash and joint pain after exposure to cold, and other common symptoms including conjunctivitis and muscle pain. The average time to onset of symptoms after exposure to cold is 1-2 hours. Significant changes in temperature can also cause seizures, which last for a short period of time, usually less than 24 hours. These symptoms are self-limiting and can be improved without treatment. Patients often complain that if the night is warm, the symptoms will be lighter the next morning, but if the symptoms are worse during the day, the symptoms will worsen. The disease develops earlier, usually at birth or within 6 months after birth. In the onset of inflammation, inflammatory markers can be detected in the blood. The quality of life of FCAS patients varies with the frequency and severity of symptoms. Late complications such as deafness and amyloidosis are rare.
The clinical features of MWS are recurrent fever, rash, and inflammation of joints and eyes. Fever does not always occur, and chronic fatigue is more common.
There is no clear predisposing factor for this disease, and cold stimulation is not obvious. The course of the disease varies depending on whether the patient exhibits a typical onset of inflammation or a long-term symptom. Patients often get worse at night. The first symptoms often appear in the early postnatal period, but it is only important in childhood.
About 70% of patients develop deafness during childhood or early adulthood, and amyloidosis is the most serious complication of MWS, with approximately 25% of patients presenting in adulthood. Amyloid is a special protein associated with inflammatory reactions. It deposits in organs such as the kidneys, intestines, skin, and heart, and gradually causes organ dysfunction. Kidney damage is particularly prominent, and with the decline in kidney function, patients may develop proteinuria. Amyloidosis is not a manifestation of CAPS, and other chronic inflammatory diseases can also occur.
In the onset of inflammation, inflammatory markers can be detected in the blood, and patients with severe disease can detect inflammatory markers for a long time, and the quality of life will also be affected.
CINCA (NOMID) is the most severe condition in this group of diseases. The rash usually occurs after birth or early in the baby. One third of the patients are premature or small. Fever is intermittent, to a lesser extent, and even in some cases there is no fever. Patients often feel tired.
Bone and joint can be affected to varying degrees. About two-thirds of patients present only joint pain or swelling during the attack. However, with age, the cartilage hyperplasia, and another third of patients can have severe joints. Malformations, pain and limited mobility. The knee, ankle, wrist and elbow joints are the most frequently affected areas. The performance of joint imaging is not the same. This proliferative joint disease usually occurs before the age of three.
Central nervous system symptoms occur in almost all patients, caused by chronic aseptic meningitis (a non-infectious meningitis). These chronic inflammatory reactions lead to an increase in intracranial pressure, manifested by different symptoms such as chronic headache, vomiting, irritability, and papilledema (as seen by ophthalmoscopy). In patients with severe illness, epilepsy or cognitive impairment may occur.
Eyes can also be affected, inflammatory reactions can occur in the anterior and posterior eyeballs, and blindness can occur in adulthood. Sensorineural deafness often occurs in late childhood or adulthood. As a result of age, 25% of patients will gradually increase amyloidosis. Chronic inflammation can lead to growth retardation and delayed puberty. A detailed clinical examination of patients with CAPS reveals a large number of overlapping symptoms. Patients with MWS can develop the same symptoms as FCAS, such as cold-sensitive (frequent winter), and mild central nervous system symptoms like CINCA (NOMID), such as frequent headaches or asymptomatic papilledema. Similarly, as you age, your neurological symptoms become more pronounced. There may be mild variations in the severity of different patients in the same family, however, in patients with milder CAPS (FCAS or mild MWS), severe CINCA (NOMID) may also be present, such as proliferative joint disease or Severe neurological symptoms.
diagnosis
Before the diagnosis of the gene, CAPS relies mainly on clinical symptoms for diagnosis. FCAS and MWS, or between MWS and CINCA/NOMID, may be difficult to distinguish due to the presence of overlapping symptoms. Clinical symptoms and medical history are the basis of diagnosis. Ophthalmic examinations (with special ophthalmoscopes), cerebrospinal fluid examinations (lumbar puncture) and imaging studies can help identify.
treatment
Genetic and physiological pathology studies of CAPS have demonstrated that IL-1β, a potent inflammatory cytokine, is overexpressed in this group of diseases and plays an important role in the pathogenesis. At present, a large number of drugs that inhibit IL-1β (IL-1β antagonists) are in the development stage. The first drug used to treat this disease is anakinra, which quickly and effectively controls the inflammatory response of all CAPS patients, such as rash, fever, pain and fatigue. These treatments can also effectively improve neurological symptoms and, in some cases, even improve deafness and control amyloidosis. The dose of the drug needs to be adjusted according to the severity of the condition. Medical treatment must begin as early as possible to prevent irreversible organ damage, such as deafness or amyloidosis, caused by chronic inflammatory reactions. Anakinra needs to be injected subcutaneously every day. The local reaction at the injection site is more common, but it can be relieved over time. Linasip is another anti-IL-1 drug approved by the US Food and Drug Administration (FDA) for the treatment of FCAS or MWS patients over the age of 11. Carnaximab is also an anti-IL-1 drug that has recently been approved by the FDA and the European Food and Drug Administration (EMA) for patients with CAPS over 4 years of age. It has been confirmed that in patients with MWS, the drug is administered subcutaneously every 4-8 weeks, which can effectively control the inflammatory response. Since the disease is a hereditary disease, anti-IL-1 drugs need to be applied for a long time.
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