Version May 2024
INTRODUCTION — Cryoglobulins are classified into three types [1]. Type I cryoglobulins are composed of one monoclonal immunoglobulin (Ig; typically IgG or IgM) and are commonly seen in the setting of a lymphoproliferative disease. By contrast, mixed cryoglobulinemia syndrome (MCS) refers to the presence of either type II or type III cryoglobulins circulating in the serum, composed of polyclonal IgG bound to another immunoglobulin with rheumatoid factor activity. In type II cryoglobulinemia, this immunoglobulin with rheumatoid factor activity is monoclonal (usually IgM isotype), whereas in type III cryoglobulinemia, it is polyclonal. Types II and III cryoglobulins account for up to 90 percent of all cryoglobulinemia cases [2].
MCS can manifest clinically as a systemic vasculitis with manifestations ranging from purpura, arthralgia, and weakness to more severe neurologic and kidney involvement. Until recently, the most common cause of MCS was hepatitis C virus (HCV), but the introduction of direct-acting antiviral agents has significantly reduced the incidence of HCV-associated cryoglobulinemia [3]. Other infections, lymphoproliferative, and autoimmune disorders have also been associated with the disease.
The etiology, clinical manifestations, and diagnosis of MCS will be reviewed here. The treatment of this disorder and an overview of cryoglobulins and cryoglobulinemia are discussed separately:
●(See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
●(See "Overview of cryoglobulins and cryoglobulinemia".)
TERMINOLOGY
●Cryoglobulinemia – Cryoglobulinemia refers to the presence of cryoglobulin in a patient's serum. This term is sometimes used interchangeably with cryoglobulinemic vasculitis (or cryoglobulinemia syndrome).
●Mixed cryoglobulinemia – Mixed cryoglobulinemia refers to cryoglobulins in the serum that contain more than one immunoglobulin component (for example, immunoglobulin M [IgM] rheumatoid factor [RF] and polyclonal immunoglobulin G [IgG]).
●Mixed cryoglobulinemia syndrome – Mixed cryoglobulinemia syndrome (MCS) refers to a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. This term is generally used to distinguish the asymptomatic presence of cryoglobulins from the clinically apparent disorder with end-organ damage. MCS can be caused by either type II or type III cryoglobulins, the characteristics of which are described below.
●Essential mixed cryoglobulinemia – Essential mixed cryoglobulinemia was the traditional term for what was thought to be idiopathic vasculitis caused by circulating cryoglobulins that contain both a polyclonal IgG and an IgM RF directed against the IgG, which are called mixed cryoglobulins. It was later discovered that in most patients, this disorder is associated with chronic hepatitis C virus (HCV) infection. Therefore, this term currently refers to the very small percentage of patients with MCS in the absence of underlying disease.
Other related terms are also discussed separately. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Terminology'.)
ETIOLOGY — The most common cause of mixed cryoglobulinemia syndrome (MCS) is chronic hepatitis C virus (HCV) infection. Other causes include chronic hepatitis B virus (HBV) infection, HIV infection, autoimmune diseases, and hematologic disorders (table 1) [4].
Idiopathic — Occasionally patients have MCS with no known etiology or association with other disorders.
Infections — A variety of infections have been associated with MCS. In addition to HCV, HBV, and HIV infection, a variety of other viruses and bacterial, fungal, and parasitic infections have also been described in association with MCS:
●HCV infection – Chronic HCV infection is the most common cause of MCS, accounting for 80 to 90 percent of cases [5-9]. However, the prevalence of HCV infections varies according to geographical regions. As an example, in some parts of northern Europe, such as the Netherlands, there is a very low prevalence of HCV infection and HCV is not found in patients with MCS [10] Although hepatomegaly and chronic liver disease are common in these patients, some do not have elevated serum aminotransferase levels [8]. Thus, there may be little or no clinical evidence of active hepatitis at the time of presentation.
Most HCV-infected patients who have circulating mixed cryoglobulins do not develop vasculitis. In a study of 226 patients with chronic liver disease, 127 had HCV infection [11], and 69 HCV-infected patients (54 percent) had circulating cryoglobulins, frequently with anti-HCV antibodies and HCV RNA concentrated in the cryoprecipitates. The prevalence of circulating cryoglobulins was higher with increasing apparent duration of disease (9.8 versus 5.3 years) and the presence of cirrhosis. Only 18 (26 percent) of the patients with circulating cryoglobulins had clinical symptoms compatible with MCS. In another study that included 139 patients with HCV-related chronic liver disease and circulating cryoglobulins, approximately one-half had clinical symptoms of MCS [12].
●HBV infection – MCS is associated with HBV infection in up to 5 percent of cases [13]. In the series of 226 patients with chronic liver disease described in the preceding section, chronic HBV infection was present in 40 patients; circulating cryoglobulins were present in 15 percent (compared with 4 percent in controls) [11]. HBV-associated cryoglobulinemic vasculitis has also been described in other studies [14,15].
●HIV infection – Some cases of MCS are due to HIV infection. This relationship was illustrated in a series of 89 HIV-1-infected patients from Greece, among whom mixed cryoglobulins were detected in 24 (27 percent) [16]. Antibodies to HIV-1 were detected in all of the cryoprecipitates, and HIV-1 RNA sequences were detected in all but one of the cryoprecipitates. Nine of these patients had symptoms compatible with MCS (eg, palpable purpura, arthralgias, and mononeuritis multiplex). Only 6 of the 24 patients with circulating cryoglobulins were infected with HCV, and only three of these patients had HCV RNA sequences in the cryoprecipitate.
Autoimmune diseases — MCS has been observed in approximately 10 percent of patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis [17]. Approximately 5 to 20 percent of patients with primary Sjögren's disease may have type II cryoglobulinemia [18]; in such patients, this finding has been associated with extraglandular involvement, the development of systemic vasculitis, B cell lymphoma, and poor survival [19].
Lymphoproliferative disorders — Mixed cryoglobulinemia can occur in patients with non-Hodgkin lymphoma, although cryoglobulinemia occurring with lymphoma is usually type I (ie, associated with cryoglobulins containing only a single monoclonal immunoglobulin component). In a study of 81 patients with biopsy-proven non-hepatitis-associated cryoglobulinemic glomerulonephritis (56 percent with type II, 29 percent with type I, and 8 percent with type III cryoglobulins), an underlying hematologic condition was found in 89 percent (including 100 percent of patients with type I and 91 percent of patients with type II cryoglobulinemia). Of the patients with a hematologic condition, 35 percent had a symptomatic lymphoproliferative disorder and 65 percent had monoclonal gammopathy of renal significance [20]. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Etiopathogenesis'.)
A separate issue is the association between MCS and the development of non-Hodgkin lymphoma. In one study of 1255 HCV-infected patients with MCS, the overall risk of non-Hodgkin lymphoma was approximately 35 times higher than in the general population or 12 times higher if nonaggressive lymphomas were excluded [21]. Independent factors associated with the development of B cell non-Hodgkin lymphoma include serum cryoglobulin levels >0.6 g/L, the presence of cryoglobulinemic vasculitis, and hypogammaglobulinemia [22].
PATHOGENESIS — The pathogenesis of mixed cryoglobulinemia syndrome (MCS) is mediated by the deposition of antigen-antibody complexes in capillaries and small arterioles, and occasionally also in small arteries. The pathogenesis of MCS is discussed in detail separately. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Etiopathogenesis'.)
CLINICAL MANIFESTATIONS
Overview of typical findings — The major clinical manifestations of mixed cryoglobulinemia syndrome (MCS) include palpable purpura (which is a major finding suggesting some form of small vessel vasculitis) (picture 1), kidney disease, arthralgias or arthritis, nonspecific systemic symptoms including weakness, peripheral neuropathy, and hypocomplementemia (with the fall in C4 levels often being most prominent) [7,9,23-26]. Patients may present with various combinations of these features, and different manifestations may predominate at different times in an individual patient.
A review of 231 patients with MCS followed in an Italian rheumatology clinic reported the following clinical findings at presentation and during follow-up [26]:
●The most common clinical features at presentation were purpura (81 percent, with skin ulcers in 11 percent), weakness and fatigue (80 percent), arthralgia (72 percent), and frank arthritis (8 percent) [26]. The clinical triad of purpura, weakness, and arthralgia ("Meltzer's triad") was present early in the course in almost 80 percent of patients.
●Peripheral neuropathy was present in 58 percent, typically with a mild peripheral sensorimotor pattern. A minority of these patients progressed to more severe neuropathy.
●Kidney involvement was present in 20 percent and eventually developed in 30 percent.
●Mild to moderate liver involvement was present in 58 percent and eventually developed in 77 percent, including some patients who advanced to cirrhosis.
●Raynaud phenomenon was present in 36 percent, and sicca symptoms were present in 29 percent.
●Laboratory testing revealed type II cryoglobulinemia in 62 percent and type III cryoglobulinemia in 38 percent. Rheumatoid factor [RF] was found in all patients, and most had hypocomplementemia, typically with very low C4 levels. Evidence of hepatitis C virus (HCV) infection was found in 92 percent of patients, and hepatitis B virus (HBV) DNA was detected in only 1.8 percent of patients.
●The clinical features were similar in patients with type II and type III mixed cryoglobulinemia syndrome, except for more frequent sicca symptoms in the latter group.
Specific organ involvement
Cutaneous involvement — Cutaneous manifestations develop in nearly all patients with MCS [1,9,24,27,28] and may precede extracutaneous manifestations by decades. Typically, these lesions consist of erythematous macules and purpuric papules of the lower extremities (90 to 95 percent) (picture 2), though infarction, hemorrhagic crusts, and ulcers also occur (10 to 25 percent). Postinflammatory hyperpigmentation (30 to 50 percent) and exacerbation as a result of cold exposure (10 to 30 percent) are common. Morphologic abnormalities of the nailfold vasculature, including tortuosity and apical enlargement, are seen on capillaroscopy [29].
Musculoskeletal involvement — Musculoskeletal complaints such as arthralgias and myalgias are common in patients with MCS, but frank arthritis or myositis is rare [13,30,31]. Arthralgias are typically described in over 70 percent of patients, especially affecting the metacarpophalangeal and proximal phalangeal joints, knees, and ankles, often in type III cryoglobulinemia and often exacerbated by cold exposure.
Peripheral nerve involvement — Neuropathy affects a high percentage of patients with MCS. Electromyographic and nerve conduction studies have demonstrated the presence of peripheral neuropathy in over 70 to 80 percent of patients with mixed cryoglobulins [32-34], but many symptom-based demographic studies report prevalences of only 30 to 45 percent. Severe peripheral neuropathy, such as mononeuropathy multiplex or combined sensorimotor disease, is uncommon [35-37]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Patterns of nerve involvement'.)
Kidney involvement — Evidence of kidney disease, typically membranoproliferative glomerulonephritis, is apparent at presentation in approximately 20 percent of patients with MCS, with an additional 10 to 30 percent developing kidney disease during follow-up [9,25,26,38-40]. On average, kidney disease is detected approximately 2.5 years after disease onset [25] (see "Overview of kidney disease associated with hepatitis C virus infection"). It is most common in the setting of type II cryoglobulinemia [13]. On the other hand, glomerular involvement occurs in less than 10 percent of cases of type III cryoglobulinemia [41].
The clinical presentation of the kidney disease is variable. The following kidney presentations were noted in a review of 146 patients with HCV-related MCS with glomerulonephritis [25]:
●Microscopic hematuria and subnephrotic proteinuria with or without chronic kidney disease – 41 percent
●Nephrotic syndrome with or without chronic kidney disease – 22 percent
●Acute glomerulonephritis – 14 percent
●Chronic kidney disease without significant urinalysis abnormalities – 13 percent
●Acute kidney injury – 9 percent
●Hypertension (which can be severe) – approximately 65 percent
The kidney presentations were similar in patients with type II and type III MCS.
The presence of kidney disease is a major factor in determining the long-term prognosis of patients with MCS. Risk factors for progression of the kidney disease are similar to those noted in other forms of glomerular disease: an elevated serum creatinine, higher rates of proteinuria, and older age [25]. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
Pulmonary involvement — Subclinical pulmonary manifestations appear to be common in MCS [42-44]. Pulmonary function tests often reveal evidence of small airways disease and impairment of gas exchange, with symptoms in approximately 10 to 20 percent of patients, usually ranging from dyspnea to cough and pleurisy. Organizing pneumonia, alveolar hemorrhage, and pulmonary vasculitis have been reported but appear to be very uncommon.
Other manifestations — Other manifestations have been reported with varying frequency, such as lymphadenopathy in up to 20 percent, splenomegaly in up to 30 percent, and abdominal pain in up to 20 percent (which sometimes reflects active mesenteric vasculitis) [31,45]. Manifestations such as hepatomegaly, abnormal liver function tests, or abnormal liver biopsy in up to 90 percent are not related to the cryoglobulinemia but to the main cause (eg, HCV infection). Clinically significant vasculitis of most other internal organs, such as of the heart, central nervous system, and retinal vessels, rarely complicates MCS. However, pathologic findings suggest that more widespread, though subclinical, involvement may be more frequent.
Some patients with MCS share a number of symptoms common to patients with sicca syndrome and primary Sjögren's disease, such as dry mouth, dry eyes, arthralgia, purpura, positive RF, and cryoglobulins. However, only a few would fulfill criteria for diagnosis of primary Sjögren's disease [4,46]. (See "Diagnosis and classification of Sjögren’s disease".)
DIAGNOSIS — The diagnosis of mixed cryoglobulinemia syndrome (MCS) is typically made from the history, typical manifestations of the disease (such as purpura, arthralgias, weakness), and the laboratory detection of serum cryoglobulins. (See 'Clinical manifestations' above.)
When to suspect MCS — The diagnosis of MCS should be suspected in any patient who presents with one or more of the following clinical features:
●Palpable purpura
●Skin ulcers
●Arthralgias and/or arthritis
●Peripheral neuropathy
●Microscopic hematuria or proteinuria with or without chronic kidney disease
●Elevated serum rheumatoid factor level
●Low serum C4 complement level
The index of suspicion for MCS should be raised further if these occur in the setting of viral infection (eg, hepatitis C virus [HCV], hepatitis B virus [HBV], or HIV), connective tissue disease (eg, systemic lupus erythematosus [SLE], Sjögren's disease, or rheumatoid arthritis), monoclonal gammopathy, or lymphoproliferative disorder (eg, non-Hodgkin lymphoma). (See 'Etiology' above.)
Evaluation — In all patients suspected of having MCS (see 'When to suspect MCS' above), the initial evaluation should include a thorough history and physical examination and laboratory testing to assess for associated diseases as well as other possible comorbidities.
History and physical examination — A history and physical examination should be performed in all patients, with an assessment of the following:
●History – Patients should be questioned about the presence of constitutional symptoms (eg, fever, fatigue, weakness, weight loss), arthralgias, or myalgias. Some patients develop purpura or skin ulcerations, exacerbated by cold temperature. The presence of acute foot or wrist drop may suggest a motor neuropathy from an ischemic process. Patients should also be asked about the presence of concomitant infection, particularly with HCV, HBV, and HIV. Symptoms of other systemic rheumatic diseases, particularly SLE and systemic sclerosis (SSc), that may identify an overlap syndrome should be sought, and patients should be queried about cutaneous eruptions, photosensitivity, and Raynaud phenomenon. Patients should also be queried regarding prior or concomitant monoclonal gammopathy or hematologic malignancy (eg, non-Hodgkin lymphoma).
●Physical examination – Characteristic skin findings such as purpura, livedo reticularis, skin necrosis, or ulcers should be identified. A general physical exam should include blood pressure measurement and a neurologic and neuromuscular exam to assess for motor weakness, such as foot drop or wrist drop. Lower extremity edema may be suggestive of kidney involvement. Abnormal nailfold capillaroscopy may be suggestive of a concomitant connective tissue disease in patients who have Raynaud phenomenon. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Nailfold capillary microscopy'.)
Laboratory evaluation
Testing for cryoglobulins — All patients suspected of having MCS should undergo laboratory testing to detect the presence of serum cryoglobulins. The method used to test for and quantify cryoglobulins is discussed in detail separately. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Detection of cryoglobulins'.)
Summarized briefly, 10 to 20 mL of blood are drawn into syringes or collection tubes that have been prewarmed to 37°C without anticoagulants since anticoagulants can produce false-positive results due to cryofibrinogen or heparin-precipitable complexes. False negative results can be seen if this protocol is not followed. In cases in which cryoglobulinemia is suspected but initial results are negative, consideration should be given to drawing a new specimen that is kept warm and handled by the clinical laboratory to prevent cryoprecipitation.
Among patients with mixed cryoglobulinemia, the cryocrit (the percentage of packed cryoglobulins compared with total serum volume after centrifugation at 4°C) is generally between 2 and 7 percent in type II, between 1 and 3 percent in type III, and much higher in type I (picture 3). The cryocrit in individuals without cryoglobulinemia is close to zero, and a cryocrit over 0.5 to 1 percent or cryoglobulin concentration above 2 to 5 mg/dL is considered clinically significant [24,47,48]. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Classification'.)
If serum cryoglobulins are detected, the immunoglobulin components of the cryoprecipitate can be identified and classified by immunoelectrophoresis or immunofixation, as discussed separately. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Immunochemical analysis'.)
There is a poor correlation between the cryocrit and clinical manifestations of MCS. In addition, many patients with chronic HCV infection have mixed cryoglobulinemia without the clinical syndrome of mixed cryoglobulinemia. This was illustrated in a study of 1083 unselected patients with chronic HCV infection in which 40 percent had low concentrations of serum cryoglobulins, which were type II in 65 percent and type III in 35 percent [49]. Among the patients with cryoglobulinemia, only 2.1 percent had vasculitis and 2.5 percent had purpura.
As many as 30 to 40 percent of the patients with type II and occasional patients with type III mixed cryoglobulinemia do not have detectable circulating cryoglobulins at presentation [39]. This may be due, in part, to simple technical errors or, more frequently, to the high variability of serum levels of cryoprecipitable immune complexes between patients and within the same patient during clinical follow-up [50]. Thus, in patients with overt MCS who do not have detectable serum mixed cryoglobulins, periodic testing for cryoglobulins may be advisable. In addition, some patients who present with kidney disease do not have detectable cryoglobulins or common manifestations of MCS [20,39,40]. Laboratory tests that suggest the presence of a cryoglobulin are a positive rheumatoid factor (RF; present in approximately two-thirds of patients) together with hypocomplementemia with low C4 levels (and normal or mildly decreased C3 levels), particularly in patients with membranoproliferative glomerulonephritis on kidney biopsy. (See 'Additional laboratory testing' below.)
In some patients, immune deposits with ultrastructural features compatible with cryoglobulins can be detected on biopsy of affected tissue, such as the kidney or skin [39,40]. (See 'Tissue biopsy in selected patients' below.)
Additional laboratory testing — In addition to testing for cryoglobulins, the following laboratory tests should be performed in all patients suspected of having MCS:
●Serum creatinine level and urinalysis with urine sediment – A serum creatinine and urinalysis with urine sediment may help identify the presence of kidney involvement and the degree of injury if present. Patients with evidence of abnormal kidney function, microscopic hematuria, proteinuria, or an active urinary sediment may need further evaluation with a kidney biopsy. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)
●Complete blood count – Patients with MCS may have a temperature-dependent increase in the apparent leukocyte and platelet counts when blood samples are tested at temperatures of 30°C or less. This can result in white blood cell counts as high as 50,000/microL and a doubling of the platelet count, both of which are attributed to various sizes of precipitated cryoglobulin particles, which may be counted as white blood cells and/or platelets in automated cell counters [51,52]. This effect is increased if the sample is allowed to cool to lower temperatures and disappears if the sample is kept at body temperature. However, many hematology instruments do not allow temperature-controlled analyses. (See "Approach to the patient with thrombocytosis", section on 'Blood smear'.)
●Liver function tests – Serum aminotransferase activity, bilirubin, and albumin may help determine if underlying liver disease is present, particularly among patients with evidence of HCV or HBV infection. (See "Approach to the patient with abnormal liver biochemical and function tests".)
●Tests for HCV, HBV, and HIV – Possible infection with HCV, HBV, and HIV infection should be investigated in all patients with suspected MCS given the etiologic relationship described above. (See 'Infections' above.)
HCV RNA has been found in the liver and in peripheral blood mononuclear cells of patients with chronic liver disease in the absence of both HCV RNA and anti-HCV antibodies in the serum [53]. Rarely, whole blood or the cryoprecipitate may test positive for HCV when routinely handled serum does not because of removal of virtually all of the HCV virion from serum or plasma into the cryoprecipitate or cellular phase of blood.
Issues related to testing for these infections are discussed in detail elsewhere:
•(See "Screening and diagnosis of chronic hepatitis C virus infection".)
•(See "Hepatitis B virus: Screening and diagnosis in adults".)
•(See "Screening and diagnostic testing for HIV infection".)
●Rheumatoid factor – RF is usually present, often at high levels, in sera of patients with type II and type III mixed cryoglobulinemia. (See "Rheumatoid factor: Biology and utility of measurement".)
●Serum complement levels – Serum C4 levels are consistently and often markedly low; C3 and CH50 are frequently decreased to a lesser extent [9,54]. (See "Overview and clinical assessment of the complement system", section on 'Complement measurement'.)
●Autoantibodies – Testing for other autoantibodies should include an antinuclear antibody (ANA) test and, if positive, anti-double-stranded DNA (anti-dsDNA), anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-U1 ribonucleoprotein (RNP) antibodies. In addition, an antineutrophil cytoplasmic antibody (ANCA) test (anti-myeloperoxidase [anti-MPO] and anti-proteinase 3 [anti-PR3]) should be performed to distinguish MCS from ANCA-associated vasculitis. (See "Measurement and clinical significance of antinuclear antibodies" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
●Monoclonal protein studies – Testing for the presence of a monoclonal gammopathy should include a serum protein electrophoresis (SPEP) with immunofixation and a serum free light chain assay. Serum matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) is a more sensitive technique and allows for identification of a monoclonal IgG in cases with negative immunofixation [55]. Detection of a monoclonal protein is suggestive of a diagnosis of type I, whereas presence of a small monoclonal component can be seen in type II. Monoclonal gammopathy is rarely associated with type III cryoglobulinemia. (See "Laboratory methods for analyzing monoclonal proteins".)
Tissue biopsy in selected patients — Although the diagnosis can generally be made based on clinical and laboratory data, biopsies of affected organs can help provide histopathologic evidence of cryoglobulinemic vasculitis in cases of diagnostic uncertainty. Mixed cryoglobulinemia syndromes (types II and III) predominantly involve the skin, kidney, and peripheral nervous system. The histopathologic findings on biopsies of affected organs are described below. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Biopsy'.)
●Skin – Skin lesions in MCS most often reveal leukocytoclastic vasculitis (50 percent), less commonly inflammatory or noninflammatory purpura (10 to 20 percent) (picture 4), noninflammatory hyaline thrombosis (10 percent), or postinflammatory sequelae (10 percent). Direct immunofluorescence microscopy of acute lesions often reveals deposits of IgM, IgG, and/or C3 complement.
●Peripheral nerve – Peripheral nerve lesions in MCS typically demonstrate vasculitis, generally of the epineurial vessels [35,56-59]. Necrotizing vasculitis or demyelination may be present, with occasional deposits of immunoglobulin and/or complement [60]. Pauci-inflammatory occlusive lesions are sometimes seen as well, suggesting a primary role for neuronal ischemia in disease pathogenesis, and are more suggestive of type I cryoglobulinemia. Affected nerves often display axonal degeneration, likely secondary to disease of the vasa vasorum. Most studies have focused upon histopathology of sural nerve biopsies, which are presumed to reflect systemic neuronal damage.
●Kidney – Histologic examination of the kidney reveals a membranoproliferative glomerulonephritis in over 80 percent of patients, with both thickening of the glomerular basement membrane and cellular proliferation (picture 5) usually with abundant intracapillary infiltration of monocytes and macrophages far greater than seen in other forms of proliferative glomerulonephritis [23]. In the remaining cases, kidney biopsy will usually show an endocapillary proliferative glomerulonephritis.
Three other histologic findings are more specific for cryoglobulin-induced disease [61]:
•Intraluminal thrombi ("immune thrombi") composed of precipitated cryoglobulins on light microscopy (picture 6).
•Diffuse dominant IgM (or codominant immunoglobulin) deposition in the capillary loops on immunofluorescence microscopy (picture 7). C3 deposition is present in >80 percent of the cases.
•Subendothelial deposits on electron microscopy (picture 8) that often have a clear substructure consisting of cylinders or short microtubules measuring 10 to 25 nm in thickness, with a characteristic "comma-like" or "fingerprint" (type III cryoglobulinemia) pattern of cryoprecipitates (picture 9). Less commonly described substructures include bundles of microtubules with cross- or patch-hatched configuration (type I cryoglobulinemia) and fibrillar deposits. Subepithelial deposits are uncommon since the cryoglobulins are too large to pass through the glomerular basement membrane and enter the subepithelial space.
Establishing the diagnosis — There are no established criteria for the diagnosis of MCS. The diagnosis of MCS is typically made based upon the presence of the following:
●Demonstration of an elevated cryocrit, such as greater than 0.5 to 1 percent, or a cryoglobulin concentration greater than 5 mg/dL. (See 'Testing for cryoglobulins' above.)
●Presence of characteristic clinical features, such as palpable purpura or skin ulcers, arthralgias or arthritis, peripheral neuropathy, and evidence of kidney involvement, and a low serum C4 concentration. (See 'Clinical manifestations' above.)
Direct histologic and immunochemical evidence of cryoglobulins from pathologic specimens may provide additional evidence for the diagnosis but are not always observed or required for diagnostic purposes. As an example, tissue biopsies and histologic confirmation of the presence of cryoglobulins is not part of the classification criteria for MCS proposed by the Italian study group on cryoglobulinemia [62].
Some patients may present with nonspecific symptoms, such as weakness or arthralgias, in the presence of a serum cryoglobulin. In such cases, evidence of a low C4 serum level or a frequently associated disorder, such as HCV infection or a clinically evident systemic disease (eg, Sjögren's disease) increases the likelihood of MCS.
DIFFERENTIAL DIAGNOSIS — Patients with suspected mixed cryoglobulinemia syndrome (MCS) may present with clinical features that overlap with a number of other autoimmune and neoplastic disorders [4,50,63]. While it is beyond the scope of this review to provide a comprehensive list of all possible alternative diagnoses, we present several here:
●Other vasculitides – Other vasculitides that affect small- or medium-sized vessels may have overlapping features with MCS. These include drug-induced small vessel vasculitis (hypersensitivity vasculitis), IgA vasculitis (IgAV; Henoch-Schönlein purpura), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (eg, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome]), and infection-related vasculitis (eg, bacterial endocarditis, poststreptococcal vasculitis, and glomerulonephritis). Vasculitis associated with a connective tissue disorder (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, Sjögren's disease) may or may not be mediated by cryoglobulins. (See "Overview of and approach to the vasculitides in adults", section on 'Clinical features suggestive of systemic vasculitis'.)
●Sjögren's disease – Patients with primary Sjögren's disease may share many of the same clinical features as found in MCS, including dryness of the eyes and mouth, arthralgias, purpura, a positive serum rheumatoid factor (RF), positive serum testing for mixed cryoglobulins, and an increased risk for developing B cell lymphoma. Primary Sjögren's disease can be differentiated from MCS by the presence of specific histopathologic changes in the salivary glands and positive testing for anti-Ro/SSA and/or anti-La/SSB autoantibodies, which are rarely present in patients with MCS. Conversely, most patients with MCS have chronic hepatitis C virus (HCV) infection and a low serum C4 level, which are uncommon in patients with primary Sjögren's disease. Distinguishing between these disorders may be more difficult in patients who are HCV negative and present with symptoms common to both Sjögren's disease and MCS; such patients are thought to have an MCS-primary Sjögren's disease overlap syndrome [63]. (See "Diagnosis and classification of Sjögren’s disease".)
●Rheumatoid arthritis – In general, patients with MCS usually have a mild, nonerosive arthritis. However, some patients with HCV-associated MCS may develop an erosive, symmetrical polyarthritis that resembles that seen in patients with rheumatoid arthritis. RF testing may be positive in both MCS and rheumatoid arthritis and is therefore not useful in distinguishing these disorders. In such cases, anticyclic citrullinated peptide antibody testing, which is positive in rheumatoid arthritis but negative in MCS, may be helpful. (See "Biologic markers in the assessment of rheumatoid arthritis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Overview – Mixed cryoglobulinemia syndrome (MCS) refers to the presence of either type II or type III cryoglobulins circulating in the serum, which can manifest clinically as a systemic vasculitis with manifestations ranging from purpura, arthralgia, and weakness to more severe neurologic and kidney involvement. (See 'Introduction' above.)
●Etiology – The most common cause of MCS is chronic hepatitis C virus (HCV) infection. Other causes include chronic hepatitis B (HBV) infection, HIV infection, autoimmune diseases, and hematologic disorders (table 1). (See 'Etiology' above.)
●Pathogenesis – The pathogenesis of MCS is mediated by the deposition of antigen-antibody complexes in capillaries and small arterioles, and occasionally also in small arteries. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Etiopathogenesis'.)
●Clinical manifestations – The major clinical manifestations of MCS include palpable purpura (which is a major finding suggesting some form of small vessel vasculitis) (picture 1), kidney disease, arthralgias or arthritis, nonspecific systemic symptoms including weakness, peripheral neuropathy, and hypocomplementemia (with the fall in C4 levels often being most prominent). Patients may present with various combinations of these features, and different manifestations may predominate at different times in an individual patient. (See 'Clinical manifestations' above.)
●Diagnosis
•When to suspect MCS – The diagnosis of MCS should be suspected in any patient who presents with one or more of the following clinical features: palpable purpura, skin ulcers, arthralgias and/or arthritis, peripheral neuropathy, and/or microscopic hematuria or proteinuria with or without chronic kidney disease. The index of suspicion for MCS should be raised further if these occur in the setting of viral infection (eg, HCV, HBV, or HIV), connective tissue disease (eg, systemic lupus erythematosus [SLE], Sjögren's disease, or rheumatoid arthritis), or lymphoproliferative disorder (eg, non-Hodgkin lymphoma). (See 'When to suspect MCS' above.)
•Establishing the diagnosis – There are no established criteria for the diagnosis of MCS. The diagnosis of MCS is typically made based upon the presence of the following:
-Demonstration of an elevated cryocrit, such as greater than 0.5 to 1 percent, or a cryoglobulin concentration greater than 5 mg/dL.
-Presence of characteristic clinical features, such as palpable purpura or skin ulcers, arthralgias or arthritis, peripheral neuropathy, and evidence of kidney involvement, and a low serum C4 concentration.
Direct histologic and immunochemical evidence of cryoglobulins from pathologic specimens may provide additional evidence for the diagnosis but are not always observed or required for diagnostic purposes. Some patients may present with nonspecific symptoms, such as weakness or arthralgias, in the presence of serum mixed cryoglobulins. In such cases, evidence of a low C4 serum level or a frequently associated disorder, such as HCV infection or a clinically evident systemic disease (eg, Sjögren's disease) increases the likelihood of MCS. (See 'Establishing the diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to earlier versions of this topic review.
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