© Ferri. 2008
Received: 26 February 2008
Accepted: 16 September 2008
Published: 16 September 2008
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© Ferri. 2008
Received: 26 February 2008
Accepted: 16 September 2008
Published: 16 September 2008
Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.
Mixed cryoglobulinemia (type II or type III), cryoglobulinemic vasculitis.
Classification and clinico-pathological characteristics of different cryoglobulinemias.
Type I cryoglobulinemia
monoclonal Ig, mainly IgG, or IgM, or IgA
self-aggregation through Fc fragment of Ig
tissue histological alterations of underlying disorder
-lymphoproliferative disorders: MM, WM, CLL, B-cell NHL
monoclonal IgM (or IgG, or IgA) with RF activity (often cross-idiotype WA-mRF) and polyclonal Ig (mainly IgG)
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
oligoclonal IgM RF or mixture of poly/monoclonal IgM
(often cross-idiotype WA-mRF)
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
polyclonal mixed Ig (all isotypes) with RF activity of one polyclonal component (usually IgM)
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
-more often autoimmune disorders
The leukocytoclastic vasculitis is the histopathological hallmark of MC (Fig. 2). It may involve small- and medium-sized vessels and may be responsible for multiple organ involvement. The term 'cryoglobulinemic vasculitis' is frequently used as synonym; it better focus on the typical histopathological alterations responsible for cutaneous and visceral organ involvement [3, 10].
It has been estimated that low levels of circulating mixed cryoglobulins can be detected in over 50% of HCV-infected individuals, while overt cryoglobulinemic syndrome develops in about 5% [3, 15, 16]. Because of the wide diffusion of HCV infection worldwide, a growing incidence of HCV-related MC can be expected, especially in underdeveloped countries where HCV in the general population is rather prevalent [3, 17].
The prevalence of 'essential' MC is reported as approximately 1:100,000 but this term is now referred to a minority of MC patients. The female-to-male ratio is 3:1.
Demographic, clinico-serological and virological features of 250 mixed cryoglobulinemia (MC) patients*.
Age at disease onset, mean ± SD yrs (range)
54 ± 13 (29–72)
Disease duration, mean ± SD years (range)
12 ± 10 (1–40)
B-cell non-Hodgkin's lymphoma
Cryocrit, mean ± SD %
4.4 ± 12
Type II/type III mixed cryoglobulins
C3, mean ± SD mg/dl (normal 60–130)
93 ± 30
C4, mean ± SD mg/dl (normal 20–55)
10 ± 12
Anti-smooth muscle antibodies
Anti-extractable nuclear antigen antibodies
anti-HCV Ab ± HCV RNA, %
Skin lesions represent the most frequent manifestations of the MC [6–10, 14, 24, 25]. Orthostatic purpura is generally intermittent, the dimension and diffusion of purpuric lesions largely varied, from sporadic isolated petechias to severe vasculitic lesions, often complicated by torpid ulcers of the legs and malleolar areas (Fig. 2). In a significant proportion of patients, repeated episodes of purpura may lead to stable, often confluent areas of ochreous coloration on the legs (Fig. 2). Cutaneous manifestations, in particular orthostatic purpura and ulcers, are the direct consequence of vasculitic alterations with the possible contributions of various co-factors, in particular chronic venous insufficiency, physical stress, mainly the prolonged standing, and/or muggy weather. In addition, the contribution of hemorheological disturbances due to high cryocrit levels may also be taken in account . In this respect, the purpuric outbreaks are frequently observed late in the afternoon when highest cryocrit levels are generally observed, often in concurrence with prolonged standing .
Almost half MC patients complain of xerostomia and xerophthalmia, however, only a few cases meet the current criteria for the classification of primary Sjogren's syndrome (see 'differential diagnosis') [11, 12, 25].
Peripheral neuropathy may frequently complicate the clinical course of the MC, in the majority of cases as mild sensory neuritis [24, 25, 29, 30]. The common symptoms are paresthesias with painful and/or burning sensations in the lower limbs, often with nocturnal exacerbation. The patient quality of life may be severely compromised because of the chronicity of these symptoms along with their scarce sensibility to therapeutic attempts. In a minority of cases the peripheral neuropathy may be complicated by severe sensory-motor manifestations, which usually appeared abruptly, often as asymmetric mononeuritis; in some patients, it may complicate the alpha-interferon treatment, possibly in predisposed subjects [29–33]. Dysarthria and hemiplegia expression of central nervous system involvement are rarely reported [25, 34]; it is often difficult to distinguish these symptoms from the most common atherosclerotic manifestations.
Since HCV infection represents the underlying disorder of the MC in the vast majority of cases, overt chronic hepatitis, generally with mild-to-moderate clinical course, can be observed at any time during the natural history of the disease [24, 25]. Chronic hepatitis was found in a great number of patients (Table 2), evolving to cirrhosis in 1/4, while only 7 patients developed hepatocellular carcinoma. In few cases, especially in combination with renal involvement, liver involvement became a life-threatening complication. On the whole, the clinical course and the prognostic value of this manifestation seem to be less severe if compared to HCV-related chronic hepatitis without MC syndrome [24, 25]; similarly, hepatocellular carcinoma less frequently complicates MC syndrome compared to the whole population of HCV-positive individuals [24, 25]. These differences are quite intriguing, but very difficult to fully explain. It is possible that the light consumption of alcohol and/or the relatively low prevalence of HCV genotype 1b [24, 25] may explain, at least in part, the rather benign clinical course of liver involvement and its scarce prognostic relevance in MC series.
Membranoproliferative glomerulonephritis type 1 is another important organ involvement, which may severely affect the prognosis and survival of the disease [24, 25, 34–37]. MC-related nephropathy is a typical immune-complex-mediated glomerulonephritis, although other immunological mechanisms have also been hypothesized [24, 25, 38, 39].
Widespread vasculitis involving medium-small sized arteries, capillaries and venules with multiple organ involvement may develop in a small proportion of patients [3, 6, 10, 24, 25, 40]. This extremely severe complication may involve the skin, kidney, lungs, central nervous system, and gastrointestinal tract. In rare cases intestinal vasculitis may suddenly complicate the disease, often in patients with renal and/or liver involvement; pain simulating an acute abdomen is the presenting symptom of intestinal vasculitis. A timely diagnosis and aggressive steroid treatment are necessary for this life-threatening complication.
Interstitial lung involvement has been anecdotally observed in MC syndrome as well as in patients with isolated HCV infection [3, 25, 41–43]. Almost invariably, lung involvement in MC is characterized by subclinical alveolitis, as demonstrated by means of bronco-alveolar lavage in unselected patient series ; this condition may predispose to harmful infectious complications and, in rare cases, it may lead to clinically evident interstitial lung fibrosis. The hyperviscosity syndrome, due to high levels of serum cryoglobulins is another rare clinical manifestation of MC . Generally, there was no relationship between the severity of clinical symptoms, such as glomerulonephritis, skin ulcers, or diffuse vasculitis and the serum levels of cryoglobulins and/or hemolytic complement [3, 24, 25]. Low complement activity is almost invariably detectable in MC, with the typical pattern of low or undetectable C4 and normal or relatively normal C3 serum levels, regardless the disease activity (Table 2). Moreover, in vitro consumption of complement can be also observed due to the anti-complement activity of some cryoimmunoglobulins . Of interest, a sudden increase in C4, raised to abnormally high levels, can be observed in MC patients developing a B-cell lymphoma . The lack of correlation between circulating cryoglobulin levels and the severity/activity of MC manifestations might be explained on the basis of different hypotheses: the pathogenic role of other non-cryoprecipitable immune-complexes, their intrinsic capacity to activate the complement, and/or the in situ formation of immune-complexes, with a relative concentration of HCV virions [3, 14, 24, 25].
Some endocrinological disorders are significantly more frequent in MC patients compared to the general population [3, 12, 13, 24, 25, 46–50]. The most common thyroid disorders are autoimmune thyroiditis, subclinical hypothyroidism, and thyroid cancer; while hyperthyroidism is less frequent, generally as reversible complication of interferon treatment [51–54]. Moreover, a statistically increased incidence of diabetes mellitus has been observed in HCV-positive patients with and without MC syndrome compared to the general population [55–57]. Finally, HCV-positive males with or without cryoglobulinemic vasculitis may develop erectile dysfunction, attributable to hormonal and/or neuro-vascular alterations .
B-cell lymphoma is the most frequent neoplastic manifestation complicating MC, often as late manifestation of the MC syndrome [58–65]. This complication may be related to peripheral B-lymphocyte expansion and to lymphoid infiltrates observed in the liver and bone marrow of MC patients [19, 39, 58, 59]. In particular, these infiltrates have been regarded by some authors as "early lymphomas", since they are sustained by lymphoid components indistinguishable from those of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL) and immunocytoma (Ic) [3, 12, 25, 59]. However, unlike frank malignant lymphomas, they tend to remain unmodified for years or even decades and are followed by overt lymphoid tumors in about 10% of cases . These characteristics justify the proposed term of "monotypic lymphoproliferative disorder of undetermined significance (MLDUS)" [3, 12, 25, 59]. Interestingly enough, type II MC-related MLDUS has its highest incidence in the same geographic areas where about 30% of patients with 'idiopathic' B-cell lymphomas also display HCV-positivity, and where an increased prevalence of HCV genotype 2a/c has been observed in both MC and lymphomas [3, 12, 25, 59]. The type II MC-associated MLDUS presents two main pathological patterns; namely, the B-CLL-like and the Ic-like [3, 12, 25, 59]. In the clinical practice, it is not rare to observe the appearance of malignant B-cell lymphomas in patients with mild MC clinical course, sometimes unexpectedly during a routine evaluation. It is possible to observe a sudden decrease or disappearance of serum cryoglobulins and RF, sometimes associated with abnormally high levels of C4, as presenting symptom of complicating B-cell malignancy .
Other neoplastic manifestations, i.e. hepatocellular carcinoma or papillary thyroid cancer, are less frequently observed [3, 11, 24, 50, 59]. In this light, the MC can be regarded as a pre-neoplastic disorder ; consequently, a careful clinical monitoring is recommendable, even in the presence of mild MC syndrome [3, 11].
Soon after the discovery of hepatitis C virus (HCV) as the major etiologic agent of non-A-non-B chronic hepatitis , a possible role of HCV infection in MC was proposed independently by two pioneering reports [68, 69] showing a significantly higher prevalence of serum anti-HCV antibodies compared to the general population. This hypothesis was definitely demonstrated in 1991, when the presence of HCV RNA was detected by means of polymerase chain reaction (PCR) in 86% of Italian MC patients . Successively, an increasingly number of studies including clinico-epidemiological observations, as well as both histopathological and virological investigations (HCV RNA detection by PCR and/or in situ hybridization) have been definitely established the preeminent role of HCV in the pathogenesis of MC [8–14, 21, 25, 59, 71–76]. The prevalence of serum anti-HCV antibodies and/or HCV RNA in MC patients ranged from 70% to almost 100% among different patient populations [3, 11–13, 25]. Given the striking association between MC and HCV infection, the term 'essential' is now referred to a minority of MC patients (in Italy <5%, Fig. 5) [3, 11–13, 25].
Another important pathogenetic factor is the interaction between HCV E2 protein and CD81 molecule, a quite ubiquitary tetraspannin present on B-cells surface ; the consequence may be the strong and sustained polyclonal stimulation of B-cell compartment (Fig. 6). A following pathogenetic step of HCV-related autoimmune-lymphoproliferative disorders may be the t [14, 18] translocation observed in B-cells of HCV-infected individuals [63, 79]. Even if not definitely confirmed [80, 81], the t [14, 18] translocation might lead to abnormally elevated expression of Bcl-2 protein with consequent inhibition of apoptosis and abnormal B-cell survival. Interestingly, the relevant prevalence of t [14, 18] translocation in patients with only type C hepatitis (about 37–38%), become particularly high in patients with HCV-related cryoglobulinemic syndrome, ranging 85% in type II MC . It is possible to hypothesize that during chronic HCV infection, several factors (including the interaction between HCV E2 protein and CD81 molecule, the high viral variability, and the persistent infection of both hepatic and lymphatic cells) may favor a sustained and strong B-cell activation (Fig. 6). This latter may in turn favors the apparition of t [14, 18] translocation and Bcl-2 overexpression; the consequent B-lymphocyte expansion is responsible for autoantibody production, including the cryoglobulins [3, 11, 12, 63, 77–79]. In addition, the prolonged B cell survival may represent a predisposing condition for further genetic aberrations, which may lead to frank B-cell malignancy as late complication of MC syndrome [11, 20, 24, 82].
Of interest, HCV-driven lymphoproliferation may explain the pathogenetic role of HCV infection also in 'idiopathic' B-cell lymphomas [11, 59, 64, 65, 80]. This association was firstly described in unselected Italian patients with 'idiopathic' B-cell lymphomas  and successively confirmed by different epidemiological and laboratory studies, mainly in the same geographical areas where HCV-associated MC is commonly found .
Given its biological characteristics, HCV may be involved in a wide number of autoimmune and lymphoproliferative disorders [3, 11, 12, 63, 77–79]. Fig. 6 summarizes the main causative factors -infectious, toxic, genetic, and/or environmental- that are potentially involved in the pathogenesis of MC [11, 12, 79, 82–84]. These factors, alone or in combination, may trigger two multistep pathogenetic processes, not mutually exclusive, responsible for MC and other HCV-related disorders. The first one produces a 'benign' poly-olygoclonal B-lymphocyte proliferation responsible for organ- and non-organ-specific autoimmune disorders, including the immune-complex-mediated cryoglobulinemic vasculitis; the second one is characterized by different oncogenetic alterations, which ultimately may lead to malignant complications [11, 82]. Comparable pathogenetic mechanisms could be also hypothesized for HCV-negative MC, this intriguing clinical subset might be correlated to other infectious agents or associated to some well-known autoimmune/rheumatic or lymphoproliferetive disorders (Fig. 5, 6) . Th1-mediated tissue alterations are probably responsible for some endocrine disorders, i.e. diabetes type 2 and thyroid dysfunction, in HCV-associated MC patients . Our preliminary data suggest that HCV infection of thyrocytes, as well as of beta cells, may upregulate CXCL10 gene expression and secretion (as shown in human hepatocytes); the consequent recruitment of Th1 lymphocytes that secrete IFN-γ and TNF-α may in turn induce CXCL10 secretion by infected cells, thus perpetuating the immune cascade responsible for these endocrine disorders. All the above pathogenetic mechanisms could be also hypothesized for HCV-negative MC, this intriguing clinical subset might be correlated to other infectious agents or associated to some well-known autoimmune/rheumatic or lymphoproliferetive disorders (Fig. 5, 6) .
MC with or without overt clinical syndrome has been reported in patients with a great number of infectious agents, usually as anecdotally observations . A significant prevalence of MC has been observed in patients with human immunodeficiency virus (HIV) infection, with and without HCV co-infection . HIV alone may exert a continuous antigenic stimulation of B-lymphocytes; these latter may be responsible for type III MC production earlier in the course of HIV infection. In some patients the B-cell disorder may evolve to monoclonal MC with typical clinical syndrome. As observed for HCV infection, the prevalence of other virus-related MC seems to show a variable prevalence among patient's series from different geographical areas . Moreover, a number of clinico-epidemiological studies revealed a heterogeneous distribution of different HCV-related extra hepatic manifestations, including some autoimmune disorders such as 'primary' Sjogren's syndrome [87–98].
Proposed criteria for the classification of mixed cryoglobulinemia (MC) patients.
rheumatoid factor +
clonal B-cell infiltrates
(liver and/or bone marrow)
definite mixed cryoglobulinemia syndrome:
a) serum mixed cryoglobulins (± low C4) + purpura + leukocytoclastic vasculitis
b) serum mixed cryoglobulins (± low C4)+ 2 minor clinical symptoms
+ 2 minor serological/pathological findings
essential or secondary mixed cryoglobulinemia:
absence or presence of well-known disorders (infectious, immunological or neoplastic)
The detection of serum mixed (IgG-IgM) cryoglobulins is necessary for a correct classification of MC syndrome (Table 3, Fig. 1). Unfortunately, there are no universally accepted methodologies for cryoglobulin measurements, but simple standardized indications are often sufficient for testing cryoglobulinemia [3, 9, 23]. Since cryoglobulins present a high thermal instability, the measurement of Ig cryoprecipitate should be performed immediately in the same place where the blood is sampled. For a correct evaluation of serum cryoglobulins, it is necessary to avoid false-negative results due to Ig cold precipitation also at room temperature. For this purpose, the first steps (blood sampling, clotting, and serum separation by centrifugation) should be always carried out at 37°C and the cryocrit determination and cryoglobulin characterization at 4°C (after 7 days). The serum with cryoglobulins should be tested for reversibility of the cryoprecipitate by rewarming an aliquot at 37°C for 24 hours. Moreover, cryocrit determinations (percentage of packed cryoglobulins referred to total serum after centrifugation at +4°C; Fig. 1) should be done on blood samples without anticoagulation to avoid false-positive results due to cryofibrinogen or heparin-precipitable proteins. Without the above relatively simple precautions, not only will the quantities of cryoglobulins measured be incorrect, but the test may completely fail to even detect cryoglobulins.
After isolating and washing the cryoprecipitate, the identity of cryoglobulin components can be determined by immunoelectrophoresis or immunofixation. These analysis must be performed at 37°C to avoid precipitation and hence loss of the cryoglobulin during the procedures. More sophisticated methodologies, such immunoblotting or two-dimensional polyacrylamide gel electrophoresis, can be proposed for laboratory investigations [102–104]. While the detection of serum cryoglobulins is fundamental for the diagnosis of MC, the levels of serum cryoglobulins usually do not correlate with the severity and prognosis of the disease [3, 11, 12, 24, 25]. Very low levels of cryocrit, often difficult to quantify, can be associated with severe and/or active cryoglobulinemic syndrome; on the contrary, high cryocrit values may characterize a mild or asymptomatic disease course. In rare cases, very high cryocrit levels, possibly associated to cryogel phenomenon, can be associated to classical hyperviscosity syndrome [24, 25, 27]. On the contrary, a sudden decrease or disappearance of serum mixed cryoglobulins, with or without abnormally high levels of C4, can be regarded as alarming signal of complicating B-cell malignancy .
Clinico-diagnostic assessment of mixed cryoglobulinemia (MC) syndrome
Clinical and serological work-up at patient's first evaluation
• past clinical history, physical examination
• chest x-ray, EKG, abdominal US, blood chemistry & urinalysis
• cryoglobulin detection and characterization (see Tab. 1)
• RF, C3–C4, ANA, anti-ENA, ANCA, ASMA, AMA, anti-LKM1, others auto-Ab
• virological markers: HCV (genotyping), HBV, others
• evaluate possible comorbidities (cardiovascular, endocrine/metabolic, etc.)
• MC classification (definite, essential, secondary): see Tab. 3
Diagnosis & monitoring of major MC complications
• chronic hepatitis, cirrhosis, hepatocellular carcinoma: monitoring (every 6–12 month) of ALT, AP & liver US (biopsy, CT scan)
• glomerulonephritis: monitoring of urinalysis & serum creatinine (kidney US, biopsy)
• peripheral neuropathy: clinical monitoring; EMG
• skin ulcers: exclusion of vascular comorbidities (A-V Doppler evaluation)
• sicca syndrome: differential diagnosis with primary SS (see Fig. 7)
• arthritis: differential diagnosis with RA (see Fig. 7)
• thyroid involvement: hormones, auto-Ab, neck US, fine-needle aspiration
• B-cell lymphoma: clinical monitoring; bone marrow/lymph node biopsies, total body CT scan
The term 'essential' MC was originally referred to autonomous disease when other well known systemic, infectious or neoplastic disorders have been ruled out by means of a wide clinico-serological work-up . However, in some patients a definite diagnosis may be difficult because of the clinical polymorphism of the disease. Moreover, the association of MC with HCV infection may further complicate the differential diagnosis with other immunological HCV-related disorders: there is a frequent clinico-pathological overlapping among different HCV-related disorders. Cryoglobulinemic syndrome can represent a crossroads between some autoimmune diseases (autoimmune hepatitis, Sjögren's syndrome, polyarthritis, glomerulonephritis, thyroiditis, type 2 diabetes, etc.) and malignancies (B-cell lymphomas, hepatocellular carcinoma) [3, 11, 12, 25, 28, 87–98]. It is possible to observe in the same patient a slow progression from mild HCV-associated hepatitis to various extrahepatic manifestations (arthralgias, sicca syndrome, Raynaud's phenomenon, RF positivity, etc.), and ultimately to overt MC syndrome with typical clinico-serological manifestations. In only a minority of MC patients a malignancy may develop, generally after a long lasting follow-up period [3, 11, 12, 24, 25]. Therefore, a careful patient evaluation is necessary for a correct diagnosis of MC syndrome, particularly with regards to other RF-positive, systemic rheumatic disorders such as rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) (Fig. 7).
While arthralgias are one of the most frequent symptoms, clear signs of sinovitis are quite rare. Generally, patients develop mild, non-erosive oligoarthritis [28, 90], often sensitive to low doses of corticosteroids with or without hydroxychloroquine. In contrast, a rheumatoid-like polyarthritis is more frequent in patients with HCV-related hepatitis without MC syndrome . In patients with HCV-associated MC and symmetrical, erosive polyarthritis the diagnosis of overlapping MC/RA syndrome can be suspected. In these cases, the detection of serum anti- cyclic citrullinated peptide antibodies, markers of classical RA, may represent a useful diagnostic tool [91, 92].
Almost half MC patients complain of sicca syndrome; however, only a few cases meet the current criteria for the classification of pSS. MC and pSS may share various symptoms: xerostomia and/or xerophthalmia, arthralgias, purpura, RF and serum cryoglobulins, and the possible complication with B-cell lymphoma [3, 11, 12, 25, 87, 93–98]. However, a careful patient clinical assessment is usually sufficient for a correct diagnosis in the large majority of cases by considering some important findings: histopathological alterations of salivary glands and specific autoantibody pattern (anti-RoSSA/LaSSB) of pSS are rarely found in MC patients; conversely, HCV infection, cutaneous leukocytoclastic vasculitis, and visceral organ involvement (renal, liver) are seldom recorded in primary Sjögren's syndrome (Fig. 7). Given the above considerations, it has been recently proposed that the presence of HCV infection per se should be considered exclusion criteria for the classification of pSS [99, 100]. In rare cases in which the differential diagnosis may result very difficult, particularly in HCV-negative individuals, it might be correct to classify the disorder as overlap syndrome. However, patients with MC/pSS overlap syndrome are often characterized by more severe clinico-prognostic evolution; they show a significant low rate of anti-RoSSA/LaSSB along with a high prevalence of mixed cryoglobulinemia, hypocomplementemia, systemic autoimmune manifestations, and complicating lymphomas (94, 97, 98). In the clinical practice, this particular condition could be better regarded as vasculitic syndrome with relevant implications on the patient monitoring and treatment [11, 24, 25].
Finally, autoimmune hepatitis, the old 'lupoid' hepatitis, may be associated to HCV infection, mainly in the same countries where HCV-associated MC is more frequently found . Moreover, it may share with MC syndrome a number of extrahepatic symptoms, including serum mixed cryoglobulins . The differential diagnosis between these two conditions may be problematic: some typical features of MC (leukocytoclastic vasculitis, hypocomplementemia, glomerulonephritis), as well as the presence of serum autoantibodies commonly found in autoimmune hepatitis (anti-smooth muscle antibodies) can be taken into account.
In patients with 'essential' MC the immunosuppressive treatment, i.e. cyclophosphamide or rituximab, is still the first-line intervention (Fig. 9, 10). For HCV-associated MC, immunomodulating/immunosuppressive treatments should be considered, especially in patients with more severe complications. These treatments include steroids, low-antigen-content (LAC) diet, plasma exchange, and immunosuppressors [3, 11, 12, 24, 116–122]. In particular, both traditional plasma exchange and double-filtration plasma exchange are able to markedly reduce the levels of circulating immune-complex, especially the cryoglobulins [24, 121, 122]. Oral cyclophosphamide (50–100 mg/day for 2–6 weeks) during the tapering of apheretic sessions can reinforce the beneficial effect of plasma exchange; moreover, it can prevent the rebound phenomenon that may be observed after the aphaeresis discontinuation . Plasma exchange is particularly useful in severe MC complications such as active membranoproliferative glomerulonephritis (Fig. 8, 9, 10).
LAC-diet is a particular dietetic treatment that can improve the clearance circulating immune-complexes by restoring the activity of the reticulo-endothelial system, overloaded by large amounts of circulating cryoglobulins [122, 123]. LAC-diet has been designed to reduce the input of alimentary macromolecules crossing the mucosal barrier of the gut; some foods, particularly dairy products and eggs, present a potential antigenic activity, and consequently might be involved in the pathogenesis of some diseases in humans. The reduction of the alimentary input of macromolecules directed to mononuclear phagocytic system may improve its function in those conditions characterized by abnormal endogenous production of immune-complexes responsible for organ damage, i.e. mixed cryoglobulinemia and other immune-complex mediated diseases. An impaired function of mononuclear phagocytic system has been also demonstrated in patients with IgA nephropathy . Given the above pathogenetic considerations, LAC-diet has been usefully employed in patients with clinically mild MC symptoms and IgA nephropathy (reduction of 24-hour proteinuria). Usually, LAC-diet and/or low dosage of steroids (6-methyl-prednisolone 2–4 mg/day) may be sufficient to improve mild manifestations (arthralgias, sporadic purpura, etc.) of the MC (Fig. 8, 9, 10); patients with mild-moderate symptoms, such as palpable purpura, are particularly sensitive to the smallest variations of daily steroid dosage (1–2 mg).
In clinical practice, MC treatment should be tailored for the single patient according to the severity of clinical symptoms (Fig. 9, 10). Therefore, patients with severe vasculitic manifestations must be promptly treated with high doses of steroids and/or plasma exchange and/or cyclophosphamide or rituximab. Some recent clinical studies suggested that sequential or combined antiviral/immunosuppressive treatment could represent a rather useful therapeutic strategy [124, 125]. The rationale of such aggressive therapies could be particularly indicated in MC patients with major clinical manifestations and partial/transitory remission after standard treatments [25, 124, 125]. On the contrary, clinically asymptomatic patients usually do not need any treatment, even in the presence of high levels of cryocrit. In all cases, a careful clinical monitoring of the disease is mandatory, with particular attention to neoplastic complications. Preliminary studies suggested the synergic affect of some therapies in association with antiviral treatment, namely the cyclosporine A or tumor necrosis factor inhibitors, in the setting of chronic hepatitis type C [126–128]. These agents may contribute to viral clearance and/or to improve the immune-mediated hepatic and extrahepatic inflammatory manifestations; future clinical trials might evaluate their potential usefulness even in MC, possibly in selected patient subsets.
The natural history of MC is not predictable and strongly depends on concomitant diseases and complications and response to treatment. Morbidity due specifically to cryoglobulinemia may also be significant (infections, cardiovascular diseases, progressive renal failure, advanced neuropathy). The overall prognosis is worse in patients with renal disease, liver failure, lymphoproliferative disease, and malignancies. Mean survival is estimated to be approximately 50–60% at 10 years after diagnosis . Careful monitoring of life-threatening MC complications (mainly nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies) should be carried out in all MC patients.
MC was first described as distinct disorder in 1966 ; 25 years later the discovery of the strong association between MC and HCV infection [3, 11, 12, 25, 70] represented a decisive contribute for a better understanding of the etiopathogenetic mechanisms responsible for the disease, and consequently for an adequate therapeutic strategy.
However, the following points remain still to be clarified:
Since the etiopathogenesis of HCV-associated MC syndrome is a multifactorial and multistep process, two important aspects need further investigations: a) HCV may represent the simple triggering factor or it could also contribute to self-perpetuating mechanism of the disease: b) nature and role of other etiopathogenetic co-factors;
The etiopathogenesis of 'essential' MC syndrome;
The actual role of HCV eradication on the natural history of HCV-associated MC syndrome;
The usefulness of sequential or combined antiviral/immunesuppressive treatments compared to traditional therapeutic approach.
hepatitis C virus
B-cell chronic lymphocytic leukemia
monotypic lymphoproliferative disorder of undetermined significance
hepatitis B virus
polymerase chain reaction
very low-density lipoprotein
mucosa-associated lymphoid tissue
human immunodeficiency virus
primary Sjögren's syndrome
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