Page 260 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

234 Clodoveo Ferri, Dilia Giuggioli and Marco Sebastiani

infiltrates, which are considered to be early indolent lymphomas, are indistinguishable from
more advanced B-cell cancers that include chronic lymphocytic leukemia, small lymphocytic
lymphoma, and immunocytoma [1, 4, 12]. While the majority of affected patients remain
stable for years, overt B-NHL is observed in approximately 10% of affected patients most
often late in the course of CV [1, 4-6, 12]. Other neoplastic manifestations, including
hepatocellular carcinoma and papillary thyroid cancer occur in the natural progression of CV
[1, 4, 12]. Accordingly, MC may be considered in part, a pre-neoplastic disorder in which
careful clinical monitoring is recommended even when the severity of MCs is mild.

Diagnosis

There are no standardized methodologies for the measurement of cryoglobulin levels
[1, 4] nor have the diagnostic criteria for CV been prospectively validated. In 1966, Meltzer
and Franklin [2] described EMCs in patients with the triad of purpura, weakness, and
arthralgia, circulating MC, low C4 levels, LCV of arterioles, capillaries and venules, and
multiorgan involvement without discernible infectious, autoimmune, or systemic involvement
[1-6]. Recent classification criteria for CV were developed by a cooperative multicenter study
using a standardized methodology [15]. When formally validated in MC patients referred to
experts from a larger number of countries, these criteria may be usefully employed in
epidemiological and clinical-pathogenic studies, and prospective therapeutic trials. Evidence
of MC in the serum of patients with suspected CV is necessary for a definite classification of
the disease [15].

Differential Diagnosis

Figure 3 describes aspects of the differential diagnosis of CV which shares a number of
etiopathogenic events with HCV infectious-related disorders including the triggering effect of
HCV, and primary autoimmune rheumatologic disorders including primary Sjögren syndrome
(pSS), polyarthritis, autoimmune hepatitis , and B-NHL [1, 4, 12]. Therefore, a differential
diagnosis should be carefully made in all patients with cryoglobulinemia and different
autoimmune manifestations. A correct disease classification may decisively affect the overall
clinical therapeutic approach and outcome. The presence of HCV in the large majority of
individuals with CV may nonetheless lead to difficulty in the differentiation of CV from
patients with hepatic and extrahepatic manifestations of HCV alone, so noted in the HCV
syndrome [12]. Such patients develop slow progression from mild HCV-associated hepatitis
to various extrahepatic manifestations including arthralgia, RF-positive arthritis, sicca
syndrome, Raynaud phenomenon, and others to clinically apparent cryoglobulinemic
syndrome. A minority of patients with long-lasting CV develop a clinically significant
malignant neoplasia.

Patients with mild CV complain of arthralgia without synovitis [1, 4, 16] while those with
HCV-associated CV and symmetrical erosive polyarthritis are more likely to have the
syndrome of overlapping CV-rheumatoid arthritis further definable by serum anti-cyclic
citrullinated peptide (CCP) IgG antibodies and RF serology.

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