Cryoglobulinemia

Since the first description of cryoglobulinemia in association with the clinical triad of purpura, joint pain, and weakness by Meltzer et al. in 1966, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia (cryoglobulinemic disease that is unassociated with an underlying disorder) has fallen. Currently, most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes the subtypes of cryoglobulinemic diseases based on two factors: the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorders. The following table lists these three types of cryoglobulinemic disease, characterized by the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, the percentage of total cryoglobulinemic disease cases, and class of disorders associated with each type. The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have rheumatoid factor activity, meaning they bind to polyclonal immunoglobulins and activate the blood complement system. They therefore form tissue deposits that contain IgM, IgG or, rarely, IgA, and components of the complement system, including in particular complement component 4. Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease. The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease. Furthermore, it has also been proposed that some of the type III cases associated with the expression of low levels of one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease. == Signs and symptoms ==

The clinical features of cryoglobulinemic disease can appear due to the circulation of cryoglobulins. They can also appear due to an underlying hematological disorder, infectious disease, or autoimmune syndrome that contributed to the cryoglobulinemia. Clinical symptoms are diverse, as cryoglobulinemia may affect any organ system. Type 1 cryoglobulinemic disease usually presents with skin findings linked to external cold temperatures whereas skin findings in type 2 and 3 disease are linked to physical exertion or prolonged standing. Extremity hypoperfusion in type 1 disease may cause Raynaud phenomenon or damage to extremities, such as fingers, hands and toes. Type I cryoglobulinemic disease Signs and symptoms due to the cryoglobulins of type I disease reflect the hyperviscosity and deposition of cryoglobulins within the blood vessels which form blood clots, which reduce or stop blood perfusion to tissues. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, blue discoloration of the arms or legs (acrocyanosis), necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, inadequate levels of oxygen in the blood (hypoxemia), and congestive heart failure. While the glomerulonephritis occurring in mixed disease appears to be due to inflammatory vasculitis, the glomerulonephritis occurring in type I disease appears due to the interruption of blood flow. == Mechanism ==

Cryoglobulins Cryoglobulins consist of one or more of the following components: monoclonal or polyclonal IgM, IgG, IgA antibodies, monoclonal κ, or λ free light chain portions of these antibodies, and proteins of the blood complement system, particularly complement component 4 (C4). The particular components involved are a reflection of the disorders that are associated with, and considered to be the cause of, the cryoglobulinemic disease. The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows: • Monoclonal IgM-based cryoglobulin occurs in cases of Waldenström's macroglobulinemia and the pre-malignant precursors to this cancer, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenstrom's macroglobulinemia. • Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection, and, less commonly or rarely, with cases of other infectious diseases such as hepatitis B infection, hepatitis A infection, cytomegalovirus infection, Epstein–Barr virus infection, Lyme disease, syphilis, lepromatous leprosy, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, coccidioidomycosis, malaria, schistosomiasis, echinococcosis, toxoplasmosis, and Kala-azar. These mixed-protein cryoglobulins are also associated with autoimmune diseases, particularly Sjögren syndrome, less commonly systemic lupus erythematosus and rheumatoid arthritis, and rarely polyarteritis nodosa, systemic sclerosis, temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses rheumatoid factor activity, and therefore binds to the Fc region of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM and IgG or IgG and complement components, particularly complement component 4 (C4). • In mixed disease (type 2 or 3 cryoglobulinemia) over 50% of cases are due to systemic lupus erythematosus and Sjogren's syndrome and less commonly other autoimmune diseases. Hepatitis C is less prevalent as a cause of mixed disease owing to effective viral treatments for hepatitis C. Successful cure of hepatitis C usually resolves type 2 or 3 mixed cryoglobulinemic disease. However, 12.6% of people may have relapsed cryoglobulinemic disease after treatment of hepatitis C. In this case, persistent circulating cryoglobulins after successful hepatitis C treatment indicates persistent disease. == Diagnosis ==

Cold induced precipitates on serum testing, hypergammaglobulinemia (with a monoclonal spike on serum protein electrophoresis in Type 1 disease with monoclonal immunoglobulins or the monoclonal component of type 2 disease), compliment consumption (low C4 and CH50 levels) in types 2 and 3 disease and rheumatoid factor activity (in types 2 or 3 disease) along with clinical signs and symptoms suggest a diagnosis of cryoglobulinemia. These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e.g., dysfibrinogenemia and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens), purpura fulminans, cholesterol emboli, warfarin necrosis, ecthyma gangrenosum, and various hypercoagulable states. Rheumatoid factor is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by immunoelectrophoresis and immunofixation to detect and quantify the presence of monoclonal IgG, IgM, IgA, κ light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and hepatitis C antigen. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryofibrinogenemia, fibrinogen deposition). In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each case's clinical findings. Biopsy of tissues in type 2 or 3 (mixed) disease usually shows a lymphocytic infiltrate of small blood vessels with no polymorphonuclear leukocytes, macrophages, or blood vessel wall destruction, distinguishing it from other causes of vasculitis. == Treatment ==

All patients with symptomatic cryoglobulinemia are advised to protect their extremities from exposure to cold temperatures, especially refrigerators, freezers, and air-conditioning. Such exposure can be very dangerous. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be monitored closely for any signs of developing cryoglobulinemic disease. Severely symptomatic cryoglobulinemic disease People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins. Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e.g., stroke, mental impairment, and myelitis) and/or cardiovascular (e.g., congestive heart failure, myocardial infarction) disturbances; vasculitis-driven intestinal ischemia, intestinal perforation, cholecystitis, or pancreatitis, causing acute abdominal pain, general malaise, fever, and/or bloody bowel movements; vasculitis-driven pulmonary disturbances (e.g., coughing up blood, acute respiratory failure, X-ray evidence of diffuse pulmonary infiltrates caused by diffuse alveolar hemorrhage); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis. Along with this urgent treatment, severely symptomatic patients are commonly started on therapy to treat any underlying disease; this treatment is often supplemented with anti-inflammatory drugs such as corticosteroids (e.g., dexamethasone) and/or immunosuppressive drugs. Cases where no underlying disease is known are also often treated with corticosteroid and immunosuppressive medications. Type I cryoglobulinemic disease Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (such as plasma cell dyscrasia, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia). This involves appropriate chemotherapy regimens which may include bortezomib (which promotes cell death by apoptosis in cells accumulating immunoglobulins) in patients with monoclonal immunoglobulin-induced kidney failure and rituximab (an antibody directed against CD20 surface antigen-bearing lymphocytes) in patients with Waldenstroms macroglobulinemia. Plasma exchanges may also be used. Bortezomib, anti-CD38 drugs such as daratumumab and isatuximab or immunosuppression with lenalidomide or thalidomide may be used in IgA or IgG disease, but treatment strategies are not well established and based on limited data or expert opinion. Treating the underlying malignancy in type 1 disease is associated with symptom improvement and a 50% rate of resolution of cryoglobulins. The 5 year survival rate of type 1 disease has been relatively unchanged, ranging from 77-83% from 1983 to 2018. Type II and III cryoglobulinemic disease Treatment of mixed cryoglobulinemic disease is, similar to type I disease, directed toward treating any underlying disorder. This includes malignant (particularly Waldenström's macroglobulinemia in type II disease), infectious, or autoimmune diseases in type II and III disease. The most effective therapy for hepatitis C-associated cryoglobulinemic disease consists of a combination of anti-viral drugs directed against hepatitis C and rituximab can be added to deplete B cells in severe or refractory disease. Data on the treatment of infectious causes other than hepatitis C for mixed disease are limited. A current recommendation treats the underlying disease with appropriate antiviral, anti-bacterial, or anti-fungal agents, if available; in cases refractory to an appropriate drug, the addition of immunosuppressive drugs to the therapeutic regimen may improve results. Mixed cryoglobulinemic disease associated with autoimmune disorders is treated with immunosuppressive drugs: a combination of a corticosteroid with either cyclophosphamide, azathioprine, or mycophenolate or combination of a corticosteroid with rituximab have been used successfully to treat mixed cryoglobulinemic disease associated with autoimmune disorders. == See also ==