Clinical manifestations

Skin manifestations are the most frequent and typical symptoms of the MC (Table 1, Figs. 3 and 4). Orthostatic purpura is usually intermittent, the dimension and diffusion of skin lesions largely vary, from sporadic, isolated petechias to severe vasculitic lesions, often complicated by torpid ulcers of the legs and malleolar areas (Figs. 3 and 4). After repeated episodes of purpura two-third of patients showed characteristic, often confluent areas of ochreous coloration on the legs. Besides the vasculitic mechanism, various co-factors, in particular chronic venous insufficiency, physical stress, such as prolonged standing, and/or muggy weather may trigger orthostatic purpura.

Arthralgias represent another frequent symptom of MC, while clinically overt arthritis is quite rare. Some patients show mild, non-erosive oligoarthritis, which is often sensitive to low doses of steroids with or without hydroxychloroquine. (Ferri et al., 2002a, 2004; Fadda et al., 2002; Ramos-Casals et al., 2001).

MC patients may complain of xerostomia and xerophthalmia; however, only a few cases meet the current criteria for the classification of primary Sjogren's syndrome (Ferri et al., 2002a, 2004).

Peripheral neuropathy, more often presenting as mild sensory neuritis, is a frequent complication of the MC (Ferri et al., 1992, 2002a, 2004), it is secondary to vasculitis of vasa nervorum and/or direct autoimmune nerve injury (Ferri et al., 1992, 2002a, 2004; Olivieri et al., 2003; Invernizzi et al., 1983). Usually, MC patients complained of pares-thesias with painful and/or burning sensations in the lower limbs, often with nocturnal exacerbation. The chronicity of these symptoms along with their lack of response to common treatments may severely affect the quality of life of these patients. Peripheral motor neuropathy usually appeared abruptly, often as asymmetric mononeuritis and it may complicate the alpha-interferon treatment in some patients (Ferri et al., 2002a, 2004). The central nervous system involvement with dysar-thria and hemiplegia is rare and often difficult to distinguish from the most common atherosclerotic manifestations (Ferri et al., 2002a, 2004).

Overt chronic hepatitis, generally with mildmoderate clinical course, can be observed at any time during the natural history of the disease. Liver involvement may evolve to cirrhosis in about 25% of cases, while only few patients develop he-patocellular carcinoma. However, in some individuals chronic hepatitis became a life-threatening complication, particularly in combination with renal involvement (Ferri et al., 2004). Membrano-proliferative glomerulonephritis type I is one of the most important organ involvement, which may severely affect the prognosis and survival of the MC (Ferri et al., 2002a, 2004).

Widespread vasculitis involving medium-small sized arteries is observed in a minority of patients (2) (Ferri et al., 2002a, 2004; Agnello and Abel, 1997). This is an extremely severe complication, which may involve the skin, kidney, lungs, central nervous system, and/or gastrointestinal tract. Abdominal pain, simulating an acute abdomen, is the present symptom of intestinal vasculitis. A timely diagnosis and high-dosage steroid treatment are necessary for this life-threatening complication (Ferri et al., 2002a, 2004).

Interstitial lung involvement has been anecdo-tally observed in HCV-positive patients with or without MC syndrome (Ferri et al., 1997, 2002a, 2004). This complication is characterized by sub-clinical alveolitis, as demonstrated by means of bronco-alveolar lavage in unselected MC patient series (Salaffi et al., 1996). In rare cases, this generally mild manifestation may lead to clinically evident interstitial lung fibrosis (Ferri et al., 1997).

Some endocrine gland dysfunction can be observed in a significantly higher number of MC patients compared with age- and sex-matched controls; in particular, diabetes mellitus type II, thyroid, and gonadal dysfunction (Ferri et al., 2002a, 2004; Antonelli et al., 1999, 2004).

Hyperviscosity syndrome due to high levels of serum cryoglobulins is rare (Ferri et al., 1990). In general, there is no relationship between the severity of MC manifestations, such as glomerulo-nephritis, skin ulcers, or diffuse vasculitis and the serum levels of complement or cryoglobulins. Hemolytic complement activity is almost invariably depressed, showing the typical pattern of low or undetectable C4 and normal or relatively normal C3 serum levels. The level of circulating cryo-globulins rarely correlates with the MC features. This observation 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 pathogenic immune-complexes, with a relative concentration of HCV virions (Ferri et al., 2002a, 2004; Abel et al., 1993).

The B-cell lymphomas represent the most frequent neoplastic complication of MC (Ferri et al., 2000, 2002a, 2004). Other neoplastic complications of MC, i.e. hepatocellular carcinoma and papillary thyroid cancer, are less frequently observed, often as late manifestations of the MC syndrome (Ferri et al., 1996, 2000, 2002a, 2004; Antonelli et al., 1999). In this light, the MC can be regarded as a pre-neoplastic disorder (Ferri et al., 2000, 2002a, 2004).

One or more serum autoantibodies can be detected in over half patients, more frequently low titer anti-nuclear (ANA, diffuse pattern) and/or anti-mitocondrial (AMA), and/or anti-smooth muscle (ASMA), without any relationship with other clinico-serological parameters. Serum anti-HCV antibodies, almost invariably associated to HCV RNA, are detectable in the large majority of MC patients (Ferri et al., 1991, 2002a, 2004). Conversely, markers of HBV infection can be detected in over one-third of patients often associated with HCV infection, while isolated ongoing HBV infection is rare (Ferri et al. 1991, 2002a, 2004).

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