Primary mixed cryoglobulinemia (essential mixed cryoglobulinemiaEMC), also known as purpura-arthralgia-cryoglobulinemia syndrome, is clinically characterized by purpuric skin lesions, arthralgia, anemia, renal damage, and hypergammaglobulinemiaMeltzer (1966) was the first to describe this disease systematically on the basis of Wintrobe (1933) and Iener( Meltzer (1966) made the first systematic description of this disease on the basis of Wintrobe (1933) and Iener ( 1947), and at the same time, it was also found that myeloma and other malignant tumors could also be accompanied by cryoglobulinemia and present the same clinical features as this disease. Zhang Chao, Department of Rheumatology and Immunology, Xinxiang Central Hospital, Henan Province, China Introduction In addition, diseases such as subacute bacterial endocarditis, hemolytic anemia of leprosy, acute glomerulonephritis, systemic lupus erythematosus rheumatoid arthritis, and Schegelen’s syndrome can be accompanied by cryoglobulinemia, and the cryoglobulinemia accompanied by these diseases is called secondary cryoglobulinemia. The disease can occur in both sexes, but is more common in females and is more common in young adults, 25-45 years of age. The etiology of the disease is not yet determined. The etiology and pathogenesis of the disease are not yet well understood. In recent years, it has been found that the incidence of this disease is higher in people infected with hepatitis B virus, but it has been confirmed that it is a kind of autoimmune rheumatic disease in the body of autoimmune response to the formation of mixed cryoglobulin plays a decisive role in the development of the disease. The so-called cryoglobulins are protein complexes that can be reversibly agglutinated at low temperatures, and their main component is immunoglobulins, which also contain small amounts of fibrinogen, lipoproteins, collagen, complement and other serum protein components. From the immunochemical aspects of the cryoglobulin is divided into three types: Type I is monoclonal cryoglobulin type, containing two or more monoclonal antibodies, including IgA, IgG and IgM; Type II is a mixture of monoclonal and polyclonal cryoglobulin type, including IgM-IgG, IgA-IgG and IgG-IgG type, etc.; Type III is a mixed polyclonal cryoglobulin type, including IgA-IgG and IgM-IgG-IgG type; Type III mixed polyclonal cryoglobulin type, including IgA-IgG and IgM-IgG-IgG type. Primary cryoglobulinemia mainly consists of type II and type III cryoglobulins, and mixed cryoglobulins are condensed rheumatoid factor (RF), which contains IgM that acts as an antibody and binds to the Fc antigenic determinant of polyclonal IgG, forming immune complexes and immune-inflammatory reactions. Occasionally, the IgA in mixed cryoglobulins acts as an antibody and reacts with the Fc segment antigenic determinant cluster of polyclonal IgG. The IgG component of mixed cryoglobulins is a polyclonal antibody, which does not have the biological function of rheumatoid factor, and its condensation depends on the IgM contained, but the participation of IgG is necessary to cause condensation. If IgG forms complexes with specific antigens, IgG is particularly susceptible to interacting with IgM, thus demonstrating that IgG has an antigenic effect on the condensation of mixed cryoglobulins, but such antigenic effect However, this antigenic effect can only be demonstrated after the appropriate antigen has interacted with the IgG, causing structural changes in the latter. Pathogenesis The mechanism by which cryoglobulins cause disease is not well understood. Studies have demonstrated that cryoglobulins are deposited as immune complexes on the vascular wall, activating both the classical and bypass pathways of complement, causing immune vasculitis in small blood vessels and leading to ischemia of the tissues at the site of the affected vessel. Tissue ischemia is also exacerbated by dysfunction of vascular endothelial cells and increased blood viscosity, red blood cell agglutination, coagulation, and platelet function abnormalities, resulting in a series of clinical symptoms. This mechanism may also be true in diseases secondary to cryoglobulinemia such as systemic lupus erythematosus. The pathogenicity of mixed cryoglobulins also depends on their cold tolerance and ability to bind complement. Cryoglobulins that are condensable at room temperature tend to be deposited pathogenically, and mixed cryoglobulins that bind complement readily cause more immunopathologic damage. Skin biopsy reveals leukocyte-crushing vasculitis with pathologic changes of swollen endothelial cells, inflammatory degeneration and necrosis of subcutaneous capillaries, small arterioles, and small venous vessels surrounded by neutrophilic infiltration, sometimes accompanied by fibrin-like deposits. Vascular inflammatory lesions similar to those in the skin are also seen in visceral biopsies. Renal biopsies may show extensive proliferative glomerulonephritis with thickening of the basement membrane of the involved glomeruli with neutrophilic infiltration, as well as focal nephritis and membranoproliferative nephritis, but sometimes the proliferative reaction is mild.These changes are mainly due to the deposition of immune complexes formed by the involvement of cryoglobulins in the intima-vascular lining of the glomeruli.Capillary endothelial hyperplasia and eosinophilic precipitates within the basement membrane have been found in many cases, especially In patients with acute renal failure, large basal intracellular eosinophilic deposits are seen, as well as complete occlusion of the capillary lumen and fragmentation of the basement membrane, similar to the changes seen in Membranoproliferative Nephritis Health Search In other cases, there is concomitant focal fibrinoid necrotizing renal arteritis, with less severe tubular and parenchymal damage. In some cases, plasma cell and lymphocyte infiltration in the renal interstitium with fibrosis is seen. In a few cases, inclusion body crystals were seen in capillary endothelial cells. Electron microscopy showed cold crystalline inclusion bodies and fibrous and tubular structures in the subendothelial deposits of the vessels. Immunopathologic examination may show IgM, IgG, and C3 deposits within the emboli and within the vessel wall. These substances are also deposited on the basement membrane in a granular distribution, thus demonstrating the role of immunization in the pathogenesis of the disease. Clinical manifestations Early in the course of the disease, most patients only showed Raynaud’s phenomenon in the fingers or toes when they were exposed to cold or cold water, but instead of the typical Raynaud’s phenomenon of pale limbs-cyanosis-purple-red, more cases showed cyanosis as the main course of manifestation. With the development of the disease, cold fashion can appear limb pain, numbness can also have joint pain or muscle pain, and even the emergence of purpura or purple skin pattern. Skin and mucous membrane damage The most common is recurrent palpable non-thrombocytopenic purpura without itching, often distributed in the lower limbs, especially around the ankles, but also in the nose, ears, mouth and other exposed areas. Purpura is intermittent, appearing in batches, each attack can last a few days to 1 week in most cases can be recurrent for many years, and localized hyperpigmentation can be left after fading. In the ankle and other joints of the skin lesions can sometimes appear skin ulcers. Although skin lesions can be triggered by exposure to cold, trauma, prolonged standing for sports, or acute infections, it is not uncommon for symptoms to be more severe in the summer than in the winter regardless of the ambient temperature. Despite the progressive development of cryoglobulinemia, purpura may occasionally resolve spontaneously, and in many cases cold urticaria may recur. These cutaneous and mucocutaneous manifestations may sometimes be the only symptom of disease activity. Joint pain is another common early manifestation of the disease. Any joint in the body can be involved, but the hands and ankles are most commonly affected. Sometimes symptomatic episodes may be accompanied by myalgia, or even mild myalgia and weakness in the absence of joint symptoms. Symptoms in the joint muscles sometimes do not parallel the overall disease and may disappear as the disease progresses This joint lesion often has no significant morning stiffness. Kidney damage More than half of the patients show kidney involvement, some of them have edema, massive proteinuria and hypertension. Most of the patients with renal damage show acute and chronic glomerulonephritis, and a few patients may develop acute nephritis, or even uremia. Renal damage is sometimes asymptomatic, and many patients with renal damage are found to have proteinuria, hematuria, pyuria, and erythrocyte tubular urine protein, which is mainly albumin, and urine light chain and peripheral proteins are not high. Therefore, the kidneys and their function should be routinely examined during the examination of the disease. Digestive system Two thirds of patients may present with varying degrees of liver enlargement or with splenomegaly, and many more with liver function abnormalities. The majority of these patients are usually asymptomatic, with severe cases of portal hypertension due to liver disease or even cirrhosis, or acute hepatic failure. Liver biopsies often show varying degrees of hepatitis, vasculitis, cirrhosis, and fibrosis with plasma cell and lymphocyte infiltration In these patients there is a high prevalence of positivity for serum hepatitis B virus surface antigen and antibodies. Gastrointestinal vasculitis has non-localized abdominal pain, which can be induced to flare up or aggravate when exposed to cold, sometimes patients can have upper gastrointestinal bleeding or blood in stools, with a positive fecal occult blood test; diarrhea or constipation can be caused by insufficient blood supply to mesenteric arteries. Individual patients can occur atypical peptic ulcer. Neurologic About 1/3 of patients may present with central nervous system symptoms, and type III is more commonly manifested as encephalopathy, cerebral nerve palsy pyramidal tract sign, myelitis, and extrapyramidal system manifestations than patients with type I and II. These lesions are mainly caused by the deposition of cryoglobulin in the vascular wall of the central nervous system, resulting in vascular inflammation in the center, causing bruising and hemorrhage and infiltration of inflammatory cells in the area, and neural demyelination may occur. Some patients may also have multiple asymmetric peripheral neuropathies with early manifestations of sensory abnormalities, as well as dyskinesia, myasthenia gravis, hypokinesia, and electromyographic abnormalities. Other The disease may also involve the heart, manifesting as myocarditis coronary arteritis, transient pericarditis and arrhythmias, but the incidence is low and often asymptomatic. Lung involvement may manifest as interstitial fibrosis and mild pleurisy Individual cases may present with adrenocortical and pancreatic involvement, often detected by pathologic examination. Sometimes generalized superficial lymph node enlargement or lower extremity lymph node enlargement may be present. Complications The disease may overlap with Scheuglen’s syndrome, Hashimoto’s thyroiditis, and Crohn’s disease, and later in the course of the disease it may be combined with systemic infections such as tuberculosis and gram-negative bacillus infections. Edit Pathogenic diagnosis In cases of non-thrombocytopenic purpura, joint and muscle pains that appear or worsen when exposed to cold with or without nephritis, the possibility of primary cryoglobulinemia should be highly suspected, and then the diagnosis of the disease can be confirmed by measuring the positive cryoglobulin in the body. However, secondary cryoglobulinemia caused by the following diseases, such as multiple myeloma, lymphoma, primary macroglobulinemia, subacute bacterial endocarditis, infectious mononucleosis, tuberculosis, systemic lupus erythematosus, and rheumatoid arthritis, etc., should be ruled out. Finally, the immunological examination to determine the presence of IgM, IgG, IgA, and C3 in the cryoglobulins is more conducive to the determination of the immunological type of the disease. Type. Primary mixed cryoglobulinemic vasculitis – Differential diagnosis Primary cold urticaria This is an autosomal dominant disorder, partially acquired. The patient has neither cold chilling hemoglobin nor cold agglutinin and cold globulin, and develops urticaria all over the body when exposed to cold, probably due to the release of histamine from mast cells as a result of cold stimulation. There is no arthralgia, nephritis or other symptoms during the exacerbation of the disease. Cold hemolysin syndrome is caused by the presence of cold hemolysin (which is essentially an IgG antibody) in the body that binds to red blood cells at temperatures of less than 20°C under the mediation of the complement and causes hemolysis. Clinical features include chills, fever, headache, abdominal pain, nausea, vomiting, bronchial asthma, hypertension, tachycardia, generalized cold urticaria, and soy sauce-colored hemoglobinuria with acute hemolytic anemia. The Donath-Landsteiner test to identify cold hemolysin is positive, usually with a titer of 1:2 to 1:64, and the Coomb test is positive. There are usually no joint symptoms, nephritis and other systemic manifestations, and the body does not have a high level of cryoglobulin, rheumatoid factor and antinuclear antibodies are negative, and the complement level is normal. Cold agglutinin syndrome This syndrome is caused by the presence of high levels of cold agglutinin in the body, which combines with the erythrocytes in the presence of cold stimuli to cause acute hemolytic syndrome. Immunological examination confirmed: cold agglutinin belongs to the κ light chain type IgM antibody health search, has the characteristics of cold globulin, usually interacts with the I antigen, in the complement-mediated effect can cause hemolysis. Cold agglutinin syndrome is divided into acute subacute and chronic three types, the first two types are secondary to certain viral infections such as infectious mononucleosis, rubella, lymphoma and so on. The chronic type is idiopathic, and the common feature of the three types is spontaneous agglutination of red blood cells in the superficial blood vessels of the extremities, nose, ears, etc. after exposure to cold, which causes cyanosis. The cyanosis disappears after the temperature of the affected area rises in a healthy search. Blood biochemistry examination can find its own blood in less than 20 ℃ when auto-coagulation. 37 ℃ Coomb test is positive in 20 ~ 30 ℃ in the mild acidification of blood can occur after complement-dependent anemia. There is hemolytic anemia in peripheral blood, reticulocytosis, leukocytes may be elevated or decreased, thrombocytopenia, and other hemolytic tests are also positive in a few cases protein electrophoresis may show paraprotein peaks in the gamma and beta regions. In conclusion, cold hemolysin syndrome and cold agglutinin syndrome are cold hemolytic anemia, primary cryoglobulinemia is an immune complex vasculitis disease without hemolytic anemia, it is easier to distinguish. Edit this section of the examination routine examination Laboratory examination 1. blood routine and blood sedimentation Some patients have mild anemia, white blood cells may be mildly elevated or reduced. Blood viscosity increases, red blood cells are arranged in the form of string money, and most patients have faster blood sedimentation. 2. Urine routine More than half of the patients may have proteinuria, hematuria, tubular and pus cells. 3. Biochemical examination About 2/3 of the patients may have abnormal liver function, elevated serum GPT and elevated bilirubin, etc. When renal function is involved, there may be elevated BUN, elevated potassium and reduced CO2CP. Protein electrophoresis may show elevated gamma globulin. 4. Immunological examination Serum IgG and IgM are elevated, sometimes IgA is elevated and complement is lowered, and a few patients may have positive rheumatoid factor and antinuclear antibody. Some patients have cellular immunodeficiency Serum cryoglobulin assay Serum cryoglobulin assay is a specific test for this disease. 5ml of fasting venous blood is collected at room temperature, placed in a clean test tube without anticoagulant, and immediately placed in a 37℃ water bath for 1~2h to make it coagulate, and then centrifuged at 37℃, 3000r/min, and then centrifuged again under the same conditions to ensure that there are no blood cells in the serum. The serum obtained after the 2nd centrifugation was transferred into a 5 ml graduated centrifuge tube and incubated in a refrigerator at 4°C for 72 h. If there was any precipitate after cold incubation, the serum was centrifuged at 4°C and 3200 r/min for 15 min, the serum on top was removed, and then the cryoglobulin precipitate was washed with saline at 4°C, then cold centrifuged and washed, and the process was repeated 3 to 5 times until no protein could be detected in the washed supernatant at the end. Then, the cold precipitate was dissolved in 4℃ saline. Then the purified cold precipitate was dissolved in an appropriate amount of 0.05mmol/L pH 8.2 barbiturate buffer cryoglobulin quantitative and immunochemical analysis, determination of cryoglobulin contained in the IgM, IgG, IgA and C3, cryoglobulin greater than 14mg / L is positive, but it should be noted that due to the various races of the population of the region and the laboratory conditions of the cryoglobulin assay is not completely uniform. The standard value should be determined according to the actual situation. Clinical significance of cryoglobulin: ① cryoglobulin is a class of immune complexes, immune complex disease can provide a basis for diagnosis. ② many infectious diseases (such as viral hepatitis B) and autoimmune diseases (such as systemic lupus erythematosus), the appearance and disappearance of cryoglobulins and disease activity and remission have a clear relationship between the evaluation of the condition and prognosis has a certain significance ③ as a simple immune complex isolation and purification methods for antigens, antibodies and other components of the detection of the conditions have a certain theoretical significance. Other auxiliary examinations When there is lesion in the central nervous system, there may be abnormalities in electroencephalogram, brain CT and brain MRI. When the heart is involved, most patients may have ECG abnormalities. Some patients may show interstitial lung changes. Related tests : C3 pH (urine) Carbon dioxide binding capacity Immunocomplexes Immunoglobulin A Immunoglobulin G Immunoglobulin M Cryoglobulin Urine Nitrogen Antinuclear Antibodies Rheumatoid Factor Cerebrospinal Fluid Glutamate Transaminase, Glutamate Transaminase Blood Sedimentation Edit Treatment and Prevention Treatment and prevention of cryoglobulinemia varies according to the severity of the disease and the treatment for the severely ill patients should be a combination of the treatment of the primary disease and the treatment of the symptomatic disease and the treatment of the immunomodulation. In order to achieve a better effect, however, there are still problems such as unsatisfactory efficacy and high recurrence rate in the treatment. Patients should prevent cold stimulation, pay attention to warmth, and give non-steroidal anti-inflammatory and analgesic drugs for arthralgia. Lower extremity purpura patients avoid standing for a long time with Raynaud’s phenomenon can be given vasodilators such as nifedipine (cardioplegia), tolazoline and anticoagulants such as intestinal aspirin (50 ~ 100mg / d). Pathogenic treatment It has been reported that bacterial endocarditis has been improved by antimicrobial treatment with cryoglobulinemia. Therefore, if there is a clear pathogen, appropriate treatment should be given. Hepatitis C virus infection can be treated with recombinant alpha-interferon. It is administered as 30,000 U 3 times/week for 3 months, or for a longer course of up to 1 year. At least 50% of patients show clinical and serologic improvement during treatment, and some patients are prone to relapse after discontinuation of therapy. In addition, the long-term use of alpha-interferon has certain side effects that are not tolerated by some patients. Patients with lymphoproliferative disorders may also have some efficacy after α-interferon treatment. Plasma exchange Plasma exchange is an effective measure for the treatment of this disease, especially for those with severe vasculitis and important organ damage. It can effectively remove cryoglobulins and pathogens from the blood, release the closed state of the monocyte-macrophage system and restore its phagocytosis function There is no limit to the amount and frequency of plasma exchange and the interval. After plasma exchange, immunosuppressive drugs should be combined to prevent abnormal immunoglobulin rebound. Glucocorticoids and immunosuppression When the disease is severe and accompanied by progressive renal or neurological lesions, high-dose glucocorticoids such as prednisone (prednisone) 1mg/kg per day or even larger amounts should be applied. The duration of treatment is 3-6 weeks, and the dose is gradually reduced after the effect is obvious. Immunosuppressive drugs such as cyclophosphamide shock therapy can also be used, the dosage of 0.5 ~ 1.0g/m2 body surface area 3 ~ 4 weeks once should pay attention to the infectious agent should be strengthened when the pathogenic treatment. Other treatments Some people apply high-dose immunoglobulin intravenous shock therapy, the dose of 400mg/(kg・d) for 5 days because of the small number of cases, should not be evaluated. Splenectomy has also been used to achieve a certain degree of efficacy. The effectiveness of Jin Gui Ren Qi Wan in treating this disease needs to be further observed. Prophylaxis Primary mixed cryoglobulinemic vasculitis – prognosis Prophylaxis Prognosis Patients without nephritis have a better prognosis Patients die in the late stages of the disease from renal failure and infections. Avoid cold stimuli and keep warm. For patients with purpura in the lower limbs should reduce standing time. Early diagnosis, early treatment.