Cryoglobulinemic vasculitis Clodoveo Ferri and Maria Teresa Mascia

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1 Cryoglobulinemic vasculitis Clodoveo Ferri and Maria Teresa Mascia Purpose of review Cryoglobulinemic vasculitis is an immune-complexmediated systemic vasculitis involving small medium-sized vessels. A causative role of hepatitis C virus in over 80% patients has been definitively established, with heterogeneous geographical distribution. This review focuses on recent etiopathogenetic, clinico-diagnostic, and therapeutical studies. Recent findings Hepatitis C virus cannot be integrated into the host genome; it may exert a chronic stimulus to the immune system. The interaction between hepatitis C virus envelope protein E2 with B-cell CD81 receptor may increase the frequency of VDJ rearrangement in antigen-reactive B lymphocytes. One consequence is the activation of various protooncogenes, including antiapoptotic Bcl-2. The extended B-cell survival is responsible for autoantibody and immune-complex production, including mixed cryoglobulins; some malignancies, mainly B-cell lymphomas, may complicate cryoglobulinemic vasculitis. Environmental or viral/host genetic cofactors should be relevant in the pathogenesis of hepatitis C virus-related diseases. Cryoglobulinemic vasculitis may overlap with other diseases (systemic vasculitides, Sjögren s syndrome, autoimmune hepatitis, lymphoma), which should be carefully considered for a correct diagnosis and treatment. Cumulative survival of cryoglobulinemic vasculitis is significantly lower compared with the general population. Therapeutic strategies for cryoglobulinemic vasculitis include etiologic (antiviral), pathogenetic (cyclophosfamide, rituximab), or symptomatic (steroids, plasmapheresis) treatments, which should be tailored to the individual patient according to the severity/activity of clinical symptoms. Summary Cryoglobulinemic vasculitis represents a crossroads among autoimmune and lymphoproliferative disorders; as hepatitis C virus infection is the major causative factor, cryoglobulinemic vasculitis is an important model for etiopathogenetic studies of virus-related diseases. Keywords cryoglobulinemic vasculitis, hepatitis C virus, lymphoma, mixed cryoglobulinemia, Sjögren s syndrome Curr Opin Rheumatol 18: ß 2006 Lippincott Williams & Wilkins. Chair and Rheumatology Unit, Department of Internal Medicine, University of Modena e Reggio Emilia, Medical School, Modena, Italy Correspondence to Professor Clodoveo Ferri MD, Reumatologia, Università di Modena e Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, Modena, Italy Tel: ; fax: ; clferri@unimore.it Current Opinion in Rheumatology 2006, 18:54 63 Abbreviations HBV hepatitis B virus HCV hepatitis C virus ß 2006 Lippincott Williams & Wilkins Introduction Cryoglobulinemia is defined as the presence of circulating immunoglobulins that precipitate at temperatures below 378C and redissolve on re-warming [1 5]. According to cryoprecipitate composition [2], cryoglobulinemia is classified into three serological subsets: monoclonal cryoimmunoglobulinemia (type I) composed of single monoclonal immunoglobulin, mixed cryoglobulinemia containing a mixture of polyclonal IgG and mono (type II) or polyclonal (type III) IgM rheumatoid factor. Type I cryoglobulinemia, frequently associated with well known hematological disorders, is usually asymptomatic per se [2 5]. Both type II and III mixed cryoglobulinemia can be classified as essential or secondary in the absence/presence of other well defined infectious, immunological or neoplastic diseases [1 7]. Essential mixed cryoglobulinemia is traditionally classified among systemic vasculitis [1 7]. During the last 15 years there has been an increasing interest in cryoglobulinemic vasculitis due to its striking association with hepatitis C virus (HCV); this association represents one of the most promising models of virus-induced autoimmune-lymphoproliferative disorders [5 7]. This review analyzes the recent clinicopathogenetic studies and therapeutic strategies of cryoglobulinemic vasculitis. Cryoglobulinemic vasculitis The so-called essential mixed cryoglobulinemia is characterized by a typical clinical triad purpura, weakness, arthralgias and multisystem organ involvement [1 7]. The pathological hallmark of mixed cryoglobulinemia is a leucocytoclastic vasculitis of small and medium-sized vessels, due to the deposition of circulating immune complexes and complement, and is responsible for cutaneous and visceral organ involvement (Fig. 1) [1 10]. In the presence of the above clinico-serological and pathological alterations, the terms mixed cryoglobulinemia and cryoglobulinemic vasculitis refer to the same clinical syndrome. 54

2 Cryoglobulinemic vasculitis Ferri and Mascia 55 Figure 1 Leukocytoclastic vasculitis and organ involvement Cryo/noncryoprecipitable immune complexes (IgG-IgM RF,complement, HCV-LDL/VLDL) Skin/ diffuse vasculitis Leukocytoclastic vasculitis (arterioles, capillaries, venules) Nephritis peripheral neuropathy Endocrine disorders Leukocytoclastic vasculitis is the pathological hallmark of cryoglobulinemic vasculitis, responsible for various skin disorders and visceral organ involvement. It is due to small vessel deposition of circulating immune complexes, complement, with coparticipation of hepatitis C virus (HCV) particles and low/very-low-density lipoprotein receptors (LDL, VLDL). RF, rheumatoid factor. Definition/classification of cryoglobulinemic vasculitis There are no available classification/diagnostic criteria for cryoglobulinemic vasculitis. Table 1 shows the preliminary criteria proposed for cryoglobulinemic vasculitis classification [5,11 ]. In clinical practice, the main diagnostic parameters are serum mixed cryoglobulins with rheumatoid factor activity, low C4, orthostatic skin purpura, and leukocytoclastic vasculitis. Diagnostic features may also include the involvement of one or more organs, as well as clonal B-lymphocyte expansion, which represents the underlying immune-system alteration of the disease [5 7,9,10,11 ]. Etiopathogenesis of cryoglobulinemic vasculitis Given the frequent association between cryoglobulinemic vasculitis and liver involvement, a causative role of hepatotropic viruses in cryoglobulinemic vasculitis has long been hypothesized [12,13]. Hepatitis B virus (HBV) represents an etiological factor of cryoglobulinemic vasculitis in a minority of individuals (Table 2) [5,11 ]. Hepatitis C virus-related cryoglobulinemic vasculitis Following the identification of HCV [14], this agent has been suspected to play a role in cryoglobulinemic vasculitis [15]. A high prevalence (86%) of HCV viremia was demonstrated in a large series of cryoglobulinemic vasculitis patients [15]. The causative role of HCV infection in cryoglobulinemic vasculitis has been definitively established on the basis of epidemiological, pathological, and laboratory investigations [5 7,9,10,11,15,16]. As the main triggering factor of mixed cryoglobulinemia syndrome is HCV, the term essential is no longer appropriate in almost three-quarters of patients [5,11 ]. HCV has been recognized as both a hepato and lymphotropic virus [5,6,17]. The infection of lymphoid tissue may trigger a constellation of autoimmune and lymphoproliferative disorders in chronically HCV-infected individuals [5 7,9,10,11,16,18 20 ]. Circulating mixed cryoglobulins are frequently detectable in HCV-infected individuals (40 50%), whereas overt cryoglobulinemic vasculitis develops in only a minority of cases (<5%) [5,18,21 23]. There is a geographical heterogeneity in the prevalence of HCVrelated cryoglobulinemic vasculitis: this association is particularly frequent in southern Europe and rare in northern Europe, northern America, and other countries [5,24 26]. Given the quite homogeneous diffusion of HCV infection worldwide, the involvement of particular viral/host genotypes, environmental or host genetic factors should contribute to the pathogenesis of cryoglobulinemic vasculitis, as well as other autoimmunelymphoproliferative disorders (Figs 2 and 3) [5,6,9,27 29,30,31,32,33,34]. Table 1 Proposed criteria for the classification of mixed cryoglobulinaemia patients Criteria Serological Pathological Clinical Major Mixed cryoglobulins Leukocytoclastic Purpura Low C4 Vasculitis Minor Rheumatoid factorþ Clonal B-cell infiltrates Chronic hepatitis HCVþ (liver and/or bone marrow) MPGN HBVþ Peripheral neuropathy Skin ulcers Definite mixed cryoglobulinemia syndrome Serum mixed cryoglobulins (low C4) þ purpura þ leukocytoclastic vasculitis Serum mixed cryoglobulins (low C4) þ two minor clinical symptoms þ two minor serological/pathological findings Essential or secondary mixed cryoglobulinemia Absence or presence of well known disorders (infectious, immunological or neoplastic) HCVþ or HBVþ, markers of hepatitis C virus or hepatitis B virus infection (anti-hcv HCV RNA; HBV DNA or HBsAg); MPGN, membranoproliferative glomerulonephritis.

3 56 Vasculitis syndromes Table 2 Clinico-epidemiological and serological features of 231 cryoglobulinemic vasculitis patients Female/male ratio 3 Mean age at diagnosis (years) Mean disease duration (years) Purpura 98% Weakness 100% Arthralgias 98% Arthritis 6.7% Raynaud s phenomenon 48% Sicca syndrome 53% Skin ulcers 22% Peripheral neuropathy 80% Liver involvement 77% Renal involvement 30% Lung involvement 1.9% Diffuse vasculitis 6.2% Hyperviscosity syndrome 0.5% B-cell lymphoma 10% Hepatocellular carcinoma 3.3% Thyroid cancer 1% MC type II/type III ratio 1.7 Cryocrit % Rheumatoid factor 98% C4 mg% (nv 20 60) C3 mg% (nv ) Autoantibodies 56% anti-hcv Ab RNA 92% anti-hbv Ab 42% HBsAg 9% Autoantibodies: ANA and/or ENA and/or AMA and/or ASMA (see text); MC: mixed cryoglobulinemia. In addition, HCV is a positive, single-stranded RNA virus without a DNA intermediate in its replicative cycle, so that viral genomic sequences cannot be integrated into the host genome. The above considerations suggest that HCV per se might be insufficient to drive the different autoimmune-lymphoproliferative disorders observed in infected individuals. It has been hypothesized that HCV infection exerts a chronic stimulus to the immune system, which facilitates the clonal B-lymphocyte expansion [5,6]. The molecular mimicry mechanism involving Figure 2 The pathogenesis of cryoglobulinemic vasculitis Cryoglobulinemic vasculitis: pathogenetic factors HCV - genotypes (2a/c?) - HCV proteins: E2 core NS3 NS4 NS5A Host - autoantigens -CD81 - LDLreceptors - HLA antigens - sex hormones Unknown environmental factors The pathogenesis of cryoglobulinemic vasculitis may include particular hepatitis C virus (HCV) genotypes and proteins, host factors, and possibly other unknown environmental agents (see text). Figure 3 Relationship between hepatitis C virus infection (HCV) and immune-system alterations responsible for cryoglobulinemic vasculitis and other autoimmune or neoplastic disorders Viral antigens Autoantigens Molecular mimacry Autoreactive cytotoxic T cells Genetic and/or environmental factors Benign B-cell expansion Autoantibodies, RF, CIC cryoglobulins IMMUNOLOGICAL DISORDERS: arthritis, porphyria c.t., sicca s. thyroiditis, gonadal dis., diabetes, hepatitis, glomerulonephritis, lung fibrosis, etc. HCV infection HCV-E2 CD81 LYMPHOCYTES Cryoglobulinemic vasculitis T(14; 18) translocation Bcl2 activation Inhibition of apoptosis Prolonged B-cell survival Other genetic aberrations (c-myc, Bcl6, p53, etc.) B-cell lymphomas Hepatocellular carcinoma Thyroid cancer HCV infection may exert a chronic stimulus on the immune system; in particular, various pathogenetic mechanisms can be taken into account: interaction between HCV envelope protein E2 and CD81 on both hepatocytes and lymphocytes; a molecular mimicry mechanism involving HCV antigens and host autoantigens; and T(14;18) translocation commonly found in HCV-infected individuals, particularly in cryoglobulinemic vasculitis patients; the consequent activation of Bcl2 proto-oncogene may lead to prolonged B-cell survival. The benign B-lymphocyte expansion may be responsible for the production of various autoantibodies, including rheumatoid factor and cryo and noncryoprecipitable immune complexes (CICs). Consequently, various autoimmune (organ and nonorgan specific) disorders and cryoglobulinemic vasculitis may develop. The indolent B-cell proliferation underlying mixed cryoglobulinaemia may be complicated by frank malignant lymphoma in about 10% of patients. Prolonged B-cell survival may predispose to activation of other protooncogenes, which ultimately may lead to malignancies. There is a clinicoserologic and pathologic overlap among different HCV-related diseases; cryoglobulinemic vasculitis represents a crossroads between these autoimmune and neoplastic disorders. RF, rheumatoid factor; porphyria c.t., porphyria cutanea tarda. particular HCV antigens, such as NS5A and HCV core proteins [35,36], and host autoantigens can be involved in B-lymphocyte activation and autoantibody production (Fig. 2) [5]. Moreover, a significant percentage of peripheral blood lymphocytes in HCV-infected individuals, particularly cryoglobulinemic vasculitis with type II mixed cryoglobulinemia, show a t(14;18) translocation, responsible for Bcl-2 activation [5,11,37]. This proto-oncogene leads to extended B-cell survival by inhibiting the apoptosis [5,37]; consequently, B-lymphocyte expansion is responsible for a wide autoantibody production [5,6,18,21, 22,24]. Besides, HCV envelop protein E2 is able to bind the CD81 molecule expressed on both hepatocytes and B lymphocytes [38]; CD81 is a cell-surface protein that, on B cells, is part of a complex with CD21, CD19, and Leu 13. This complex reduces the threshold for B-cell

4 Cryoglobulinemic vasculitis Ferri and Mascia 57 activation; the interaction with HCV-E2 might increase the frequency of VDJ rearrangement in antigen-reactive B cells. One possible consequence could be the production of important genetic aberrations observed in HCV-infected individuals, leading in some cases to overt malignancy (Figs. 2 and 3) [5,6,11,37,39,40,41, 42,43]. Nonhepatitis C virus-related cryoglobulinemic vasculitis According to the above-mentioned geographical heterogeneous distribution of HCV-related cryoglobulinemic vasculitis, patients with HCV-negative cryoglobulinemic vasculitis are commonly found in some areas such as northern Europe [25] where the overall prevalence of the disease is significantly lower compared with the Mediterranean area [5,18,21,44]. A wide number of other infectious agents may be associated with cryoglobulinemia, often as anecdotal observations without a particular clinical relevance [3,45 49]. Trejo et al. [50] evaluated the clinical relevance of mixed cryoglobulinemia and its relationship with other systemic disorders. Among 57 patients with mixed cryoglobulinemia, HCV infection was detected in 82%, while essential mixed cryoglobulinemia was present in 7%; the remaining cases were associated with other infections or well known connective tissue diseases. We also analyzed retrospectively 195 patients with mixed cryoglobulinemia typified during 1 year at the laboratory of our hospital (M.T. Mascia, personal communication). Only 31/195 (16%) patients were HCV-negative; clinically, they showed a connective tissue disease in 18/31 (58%), essential mixed cryoglobulinemia in 9/31 (29%), malignancy in 2/31 ((6%), and other infections in 2/31 (6%). The overall evaluation of our patients with HCV-negative mixed cryoglobulinemia suggest the following considerations: essential mixed cryoglobulinemia is particularly rare and often manifests as incomplete cryoglobulinemic vasculitis syndrome; in patients with well known connective tissue disease there are only trace amounts of cryoglobulins, without typical cryoglobulinemic vasculitis syndrome, whereas high cryocrit levels were invariably associated with HCV infection; patients with Sjögren s syndrome showed higher levels of cryocrit along with cryoglobulinemic vasculitis syndrome, making it indistinguishable from that observed in HCV-positive patients. In HCV-negative cryoglobulinemic vasculitis patients an occult HCV infection should be taken into account [51], as observed in patients with persistently abnormal liver function tests of unknown etiology [52 ]. A liver biopsy [53 ] or bone marrow biopsy and long-term virological follow-up [51] may be necessary for a correct assessment. The actual prevalence of occult HCV infection in cryoglobulinemic vasculitis patients should be investigated further due to its pathogenetic and therapeutic implications. Clinical manifestations The prevalence of single cryoglobulinemic vasculitis manifestations may vary among patient series from different referral centres [5,6]. Table 2 shows the main demographic, clinico-serological, and virological features observed in a large Italian cryoglobulinemic vasculitis patient series [11 ], which is quite comparable to other reported series [5,9]. Cutaneous manifestations and arthralgias or arthritis are the most frequent symptoms [5,11,54,55 ]. Almost half of patients complained of xerostomia and xerophthalmia, but only few met the current criteria for the classification of primary Sjögren s syndrome [5,11 ]. Peripheral neuropathy is a frequent complication of cryoglobulinemic vasculitis, usually as mild sensory neuritis [5,11,56]. Sensory-motor neuropathy may appear abruptly, often as mononeuritis [5,11 ]. Central nervous system involvement with dysarthria and hemiplegia is rare and often difficult to distinguish from the most common atherosclerotic manifestations [5,11, 57,58]. Chronic hepatitis commonly shows a mild moderate clinical course; it may evolve to cirrhosis in a quarter of cases and it is rarely complicated by hepatocellular carcinoma [5,11 ]. Membranoproliferative glomerulonephritis type I is one of the most important conditions [5,11,59 ] (Table 2).By contrast, multiple organ involvement secondary to widespread vasculitis is observed in a minority of patients [3,5,7,9,11 ]. Interstitial lung fibrosis has been anecdotally observed in HCV-positive patients with or without cryoglobulinemic vasculitis syndrome; more often it is characterized by subclinical alveolitis [5,11 ]. Various endocrine gland dysfunctions can be observed in a significantly higher number of cryoglobulinemic vasculitis patients compared with age and sex-matched controls; in particular, diabetes type II, thyroid, and gonadal dysfunction [5,11,40,60,61]. Hyperviscosity syndrome due to high levels of cryoglobulins is rare [5]. Reduced hemolytic complement activity, with typical pattern of low or undetectable C4, is very frequently found; however, complement levels and cryocrit rarely correlate with the severity of cryoglobulinemic vasculitis [5,9,11 ]. B-NHL represents the most frequent neoplastic complication of cryoglobulinemic vasculitis [4,6,11,62,63, 64 ], while hepatocellular carcinoma and papillary thyroid cancer are less frequently observed (Fig. 3) [5,6, 11,40 ]. Different serum autoantibodies can be detected in over half of cryoglobulinemic vasculitis patients [5,11,65,66]. Both anti-hcv antibodies and HCV viremia are detectable in the large majority of mixed cryoglobulinemia

5 58 Vasculitis syndromes Figure 4 Overlap between primary Sjögren s syndrome (SS) and cryoglobulinemic vasculitis (CV) HCV - Cryo. vasculitis - Sjögren s S CV HCV Similarities Age,sex Sicca syndrome, Arthralgias, arthritis RF+, cryoglobulins Lymphoma Primary SS Cryoglobulinemic vasculitis vs primary Sjögren s S Differences Hepatitis, glomerulonephritis Skin and salivary gland histology Ab anti-ssa/ssb Low complement HCV infection Primary Sjögren s syndrome (SS) and cryoglobulinemic vasculitis (CV) may share some important clinico-serological features. However, the severity of istopathological pattern of salivary gland involvement and specific autoantibodies (anti-rossa/lassb) are rarely found in CV patients; conversely, cutaneous leukocytoclastic vasculitis, and visceral organ involvement (renal, liver), low C4, and HCV infection are seldom recorded in primary SS. The figure reproduces the possible overlapping of these two disorders. There is a continuum from the classical CV to primary SS, which may include (1) Primary SS with HCV-negative cryoglobulinemic vasculitis; (2) HCV-associated SS without cryoglobulinemic vasculitis; and (3) Overlap syndrome SS/cryoglobulinemic vasculitis in HCV-positive patients; due to its clinico-therapeutical implications this phenotype could be better classified as cryoglobulinemic vasculitis. RF, rheumatoid factor. patients, associated in some individuals to HBV markers, while ongoing HBV infection is rare [5,11,15]. Overlapping disorders Given its clinical polymorphism, mixed cryoglobulinemia syndrome may overlap with a variety of immunological and neoplastic diseases; in particular, other systemic vasculitides, Sjögren s syndrome, autoimmune hepatitis, and B-cell lymphoproliferative disorders (Fig. 3). Differential diagnosis with other systemic vasculitides is quite easy if clinico-serological and histopathological features are correctly evaluated. Sjögren s syndrome and cryoglobulinemic vasculitis may share various symptoms (Fig. 4) [67,68]. In large series of patients with Sjögren s syndrome, the presence of mixed cryoglobulinemia is around 20% [69,70 ]; the presence of cryoglobulinemia seems to identify a particular clinical subset of Sjögren s syndrome, characterized by a poor prognosis due to more severe internal organ involvement and frequent evolution to malignant lymphomas [69,70, ,72]. Careful patient clinical assessment is often sufficient for a correct diagnosis in the majority of cases (Fig. 4). In some patients, however, a differential diagnosis may be very difficult; therefore, it may be necessary to classify these cases as cryoglobulinemic vasculitis Sjögren s overlap syndrome [5,11,67]. An intriguing but controversial aspect is the possible etiopathogenetic role of HCV in Sjögren s syndrome [73], suggested by the well known HCV sialotropism and by a recent clinico-epidemiological study focusing on patients with HCV-associated Sjögren s syndrome [74 ]. Interestingly, these patients show a significant low rate of anti-rossa/lassb (23%) along with a high prevalence of mixed cryoglobulinemia (50%), hypocomplementemia (51%), and systemic vasculitic manifestations (58%). The authors suggest that this particular condition cannot be classified as primary Sjögren s syndrome [74 ]; in fact, at least 50% of these patients could be better classified as having typical cryoglobulinemic vasculitis syndrome. It is not surprising that, in genetically predisposed individuals, the complex immune-system alterations triggered by HCV chronic infection may produce particular phenotypes, which may meet the diagnostic criteria of well known diseases, including Sjögren s syndrome, systemic lupus, rheumatoid arthritis, and so on [5,11,18,19,54,75,76]. Patients with autoimmune hepatitis may present mixed cryoglobulins, HCV infection, and extrahepatic manifestations such as thyroiditis, sicca syndrome, or arthritis [65]. In these instances, some patognomonic findings, including high titre of specific autoantibodies (ANA, ASMA, anti-lkm1) for autoimmune hepatitis, or symptoms such as membranoproliferative glomerulonephritis or leukocytoclastic vasculitis for cryoglobulinemic vasculitis, may be useful for the differential diagnosis [11 ]. Finally, B-NHL complicating HCV-related cryoglobulinemic vasculitis can be confused with idiopathic B-NHL producing clinico-serological findings of cryoglobulinemic vasculitis (Fig. 3). The differential diagnosis of these two entities may be important, especially for its therapeutic implications: the treatment of B-cell NHL complicating the cryoglobulinemic vasculitis may need some precautions due the concomitance of HCV infection with possible liver or renal failure [11 ]. Prognosis Few clinico-prognostic studies are available in the literature [11,77,78]. The cumulative 10th year survival of mixed cryoglobulinemia patients is significantly lower compared with the age and sex-matched general population [11 ]. The worse prognostic factors are the patient s age at the time of diagnosis (>60 years), male gender, and renal involvement; however, death is often

6 Cryoglobulinemic vasculitis Ferri and Mascia 59 Figure 5 Etiopathogenetic process of hepatitis C virus (HCV)- related cryoglobulinemic vasculitis (CV) and therapeutic interventions HCV eradication Interferon-a + ribavirin Immunosuppressors Cyclophosphamide, rituximab CIC reduction Plasma exchange, LAC-diet Steroids Chemotherapy HCV infection Benign B-cell expansion autoantibodies, CIC, and cryoglobulin production Cryoglobulinemic vasculitis B-cell lymphoma Cryoglobulinemic vasculitis is the result of three main clinico-pathological alterations: chronic HCV infection, B-lymphocyte proliferation, and immune-complex-mediated vasculitis. Following the cascade of events leading from HCV infection to overt cryoglobulinemic vasculitis, we can treat the disease at different levels by means of etiologic, pathogenetic, and symptomatic often combined therapies (see text). CIC, circulating immune complex; LAC-diet, low-antigen-content diet. the result of concomitant, severe clinical manifestations [11 ]. Treatment The treatment of cryoglobulinemic vasculitis is particularly challenging because of its complex etiopathogenesis, including HCV infection, autoimmune, and lymphoproliferative alterations. We can treat the disease at different levels by means of etiological, pathogenetic, or symptomatic therapies (Figs 5 and 6) [5,6, 11,79]. Etiological treatment An attempt at HCV eradication should be done in all cases of HCV-associated cryoglobulinemic vasculitis: antiviral therapy may improve the immune-lymphoproliferative disorder underlying the disease [80,81], while combined a-interferon and ribavirin might achieve the eradication of HCV infection in a significant number of treated patients [79,82,83,84 ]. Controlled clinical trials are necessary, however, to definitively evaluate the effect of antiviral therapy in HCV-related cryoglobulinemic vasculitis. In the absence of HCV eradication, its usefulness is often transient and seldom associated with re-exacerbation or appearance of important complications, including vasculitic manifestations, peripheral sensory-motor neuropathy, rheumatoid-like polyarthritis, Figure 6 Therapeutic strategies of cryoglobulinemic vasculitis Therapeutic strategies of cryoglobulinemic vasculitis Asymptomatic monitoring Possible sequential treatment Mild moderate Purp.,weak.,arthr. mild neuropathy Moderate severe active CH, MPGN skin vasculitis low medium dose CS ± LAC-diet ± other symptomatics peg-ifn+ Riba??? peg-ifn+ Riba Severe-active manifestations: nephritis, skin ulcers, sensory-motor neuropathy, widespread vasculitis, B-lymphomas, etc. Rituximab IFN+RIBA Severe, rapidly progressive glomerulonephritis sensory-motor neuropathy widespread vasculitis Plasma exchange + CS + CFX or Rituximab Active chronic hepatitis, minor CV manifestations IFN+RIBA Rituximab Left: therapeutic strategies of HCV-related cryoglobulinemic vasculitis: the therapeutic interventions should be decided on the basis of the severity/ activity of clinical symptoms; in asymptomatic patients careful monitoring is often sufficient; in patients with moderate severe manifestations, mainly hepatitis, an attempt to eradicate the HCV infection should be carried out; severe, rapidly progressive complications should be treated with more aggressive treatments, as in other severe systemic vasculitides. Right: sequential treatment can be attempted in those individuals with serious clinical manifestations and in the absence of important contraindications. arthr., arthralgias; CFX, cyclophosphamide; CH, chronic hepatitis; CS, corticosteroid; LAC-diet, low-antigen-content diet; MPGN, membranoproliferative glomerulonephritis; peg-ifn, pegylated interferon; Purp., purpura; RIBA, ribavirin; weak., weakness.

7 60 Vasculitis syndromes endocrine disorders, and in rare cases, systemic autoimmune diseases [5,11,79,85 88]. The immunomodulating effect of a-interferon may explain its clinical efficacy in HCV-negative cryoglobulinemic vasculitis patients [89]. In the near future, a vaccine-based therapy with recombinant HCV proteins [90] may prevent the appearance of extra-hepatic complications or to interrupt the selfperpetuating autoimmune mechanism of cryoglobulinemic vasculitis. Pathogenetic/symptomatic treatments A short time course of cyclophosphamide (1 2 mg/kg body weight daily, for 2 3 months) in association with high dosage of steroids or plasma exchange may be able to treat the most severe, life-threatening complications of cryoglobulinemic vasculitis; namely, glomerulonephritis, recent onset sensory-motor neuropathy, or widespread vasculitis [11,79]. Treatment with cytotoxic drugs does not seem to affect the progression of HCV infection and, in particular, liver involvement. More recently, the use of rituximab, monoclonal anti- CD20 antibody, has been successfully employed in cryoglobulinemic vasculitis patients, without significant side effects [91,92,93,94]. Controlled clinical trials are necessary in order to verify the long-term efficacy and safety of rituximab. The impact of rituximab on HCV viremia, which increases the baseline levels twofold [92], suggests the possible use of combined/sequential therapy with monoclonal anti-cd20 antibody and antiviral agents, particularly in patients with persistent cryoglobulinemic vasculitis syndrome despite successful eradication of HCV with antiviral therapy [95,96 ] (C. Ferri, personal communication). In patients with particularly severe or resistant cryoglobulinemic vasculitis complications, some anecdotal reports suggest the possible use of other immunomodulating or biologic therapies [97 100]. Traditionally, short time courses and low dosage of corticosteroids and plasma exchange are classified as symptomatic therapies; however, they may also work as immuno-modulating or immunosuppressive treatments. Corticosteroids, alone or in association with plasma exchange or immunosuppressors [11 ], may represent the first-line intervention in the few cases of essential cryoglobulinemic vasculitis. Low-antigencontent diet can improve the serum clearance of immune complexes by restoring the activity of the reticulo-endothelial system overloaded by large amounts of circulating cryoglobulins [5,11 ]. Patients with mild polyarthritis are often responsive to low doses of steroids with or without hydroxychloroquine; more severe cases might be successfully treated with antitumor necrosis factor a or cyclosporine A. On the whole, the treatment of cryoglobulinemic vasculitis should be tailored for the single patient, according to the severity of clinical symptoms (Fig. 6) [5, 11,79]. Conclusion Cryoglobulinemic vasculitis is a multifaceted disease, clinically characterized by both autoimmune and lymphoproliferative manifestations. Since HCV infection is the major triggering factor of the disease, cryoglobulinemic vasculitis represents an important model for etiopathogenetic studies of virus-driven immunological and neoplastic disorders. Moreover, the geographical heterogeneous distribution of HCVassociated cryoglobulinemic vasculitis suggests an important role of other unknown infectious/ environtnental co-factors. A clinical overlap between cryoglobulinemic vasculitis and other diseases is quite frequent; in particular, Sjögren s syndrome, autoimmune hepatitis, B-cell lymphoma, other systemic vasculitides. Thereafter, some clinico-serological and histopathological findings should be taken into account for a correct classification/diagnosis of cryoglobulinemic vasculitis, mainly orthostatic purpura, serum mixed cryoglobulins, low C4, leukocytoclastic vasculitis. The therapeutic approach to cryoglobulinemic vasculitis is particularly difficult. An attempt to eradicate HCV infection, when present, might represent the gold standard; however, many patients are resistant to antiviral treatment or they may develop important side effects. Low-dosage of steroids may be sufficient to improve the quality of life in the majority of patients, characterized by mild disease activity. In the presence of severe, lifethreatening complications a combined treatment with immunesuppressors, steroids, and plasmapheresis can be necessary. Acknowledgements We thank all the following people who actively contributed to our studies mentioned in the present work: C. Mussini MD, M. Sebastiani MD, D. Giuggioli MD, Rheumatology Unit, University of Modena e Reggio Emilia, Italy; L. La Civita MD, G. Longombardo BS, P. Fadda MD, Rheumatology Unit, University of Pisa; Italy; AL Zignego MD, Department of Internal Medicine, University of Florence, Italy; S.A. Pileri MD, Pathologic Anatomy and Haematopathology Unit, University of Bologna, Italy. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 123). 1 Meltzer M, Franklin EC, Elias K, et al. Cryoglobulinemia: a clinical and laboratory study. II: Cryoglobulins with rheumatoid factor activity. Am J Med 1966; 40: Brouet JC, Clouvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins. Am J Med 1974; 57:

8 Cryoglobulinemic vasculitis Ferri and Mascia 61 3 Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 1980; 69: Gorevic PD, Frangione B. Mixed cryoglobulinemia cross-reactive idiotypes: implication for relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol 1991; 28: Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol 2002; 55: Ferri C, Pileri S, Zignego AL. Hepatitis C virus, B-cell disorders, and non- Hodgkin s lymphoma. In: Goedert JJ, editor. Infectious causes of cancer: targets for intervention. National Cancer Institute (NIH). Totowa, NJ: The Humana Press Inc.; p Dammacco F, Sansonno D, Piccoli C, et al. The cryoglobulins: an overview. Eur J Clin Invest 2001; 31: Bombardieri S, Ferri C, Migliorini P, et al. Cryoglobulins and immune complexes in essential mixed cryoglobulinemia. La Ricerca Clin Lab 1986; 16: Abel G, Zhang QX, Agnello V. Hepatitis C virus infection in type II mixed cryoglobulinemia. Arthritis Rheum 1993; 36: Monti G, Galli M, Invernizzi F, et al. Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. QJM 1995; 88: Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004; 33: The first follow-up study on a large Italian series of cryoglobulinemic vasculitis, reporting the 10th year survival, the main prognostic clinical features, and therapeutical aspects. In addition, the proposal of preliminary classification criteria and more recent etiopathogenetic studies are discussed. 12 Bombardieri S, Ferri C, Di Munno O, Pasero G. Liver involvement in essential mixed cryoglobulinemia. La Ricerca Clin Lab 1979; 9: Levo Y, Gorevic PD, Kassab HJ, et al. Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 1977; 296: Choo GL, Kuo G, Weiner AJ, et al. Isolation of a cdna clone derived from a blood-borne non-a non-b viral hepatitis genome. Science 1989; 244: Ferri C, La Civita L, Longombardo G, et al. Hepatitis C virus and mixed cryoglobulinemia. Eur J Clin Invest 1993; 23: Ferri C, Zignego AL. Relation between infection and autoimmunity in mixed cryoglobulinemia. Curr Opin Rheumatol 2000; 12: Ferri C, Monti M, La Civita L, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993; 82: Ramos-Casals M, Font J. Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr Opin Rheumatol 2005; 17: This review mainly focuses on the frequent overlapping between extrahepatic HCV-related disorders and some well defined systemic autoimmune autoimmune diseases. 19 Agnello V, De Rosa FG. Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol 2004; 40: A wide and updated review of the complex field of extrahepatic disorders associated with HCV infection. 20 Nissen MJ, Fontanges E, Allam Y, et al. Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon. Rheumatology (Oxford) 2005; 44: The study analyzes the clinical and serological features of 21 HCV-positive patients followed in a rheumatology department compared with 41 patients from an HCV support association. 21 Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994; 106: Pawlotsky J, Mustapha B, Andre C, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case control study. Hepatology 1994; 19: Kayali Z, Buckwold VE, Zimmermann B, Schmidt WN. Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis. Hepatology 2002; 36: Lenzi M, Johnson PJ, McFarlane IG, et al. Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity. Lancet 1991; 338ii: Weiner SM, Berg T, Berthold H, et al. A clinical and virological study of hepatitis C virus-related cryoglobulinemia in Germany. Hepatology 1998; 29: Au WY, Kwok JS, Chu KM, Ma ES. Life-threatening cryoglobulinemia in HCVnegative Southern Chinese and a novel association with structural aortic abnormalities. Ann Hematol 2005; 84: The study reports the low rate of mixed cryoglobulinemia and of its association with HCV infection in a large southern Chinese general population. 27 Lenzi M, Frisoni M, Mantovani V, et al. Haplotype HLA-B8-DR3 confers susceptibility to hepatitis C virus-related mixed cryoglobulinemia. Blood 1998; 91: Ossi E, Bordin MC, Businaro MA, et al. HLA expression in type II mixed cryoglobulinemia and chronic hepatitis C virus. Clin Exp Rheumatol 1995; 13: Zignego AL, Ferri C, Giannini C, et al. Hepatitis C virus genotype analysis in patientswithtypeiimixedcryoglobulinemia. Ann Intern Med1996;124: Zehender G, De Maddalena C, Bernini F, et al. Compartmentalization of hepatitis C virus quasispecies in blood mononuclear cells of patients with mixed cryoglobulinemic syndrome. Virology 2005; 79: An interesting pathogenetic hypothesis based on the reduced HCV quasispecies heterogeneity in cryoglobulinemic vasculitis, possibly due to HCV genotype Vassilopoulos D, Younossi ZM, Hadziyannis E, et al. Study of host and virological factors of patients with chronic HCV infection and associated laboratory or clinical autoimmune manifestations. Clin Exp Rheumatol 2003; 21 (Suppl 32):S101 S Ivanovski M, Silvestri F, Pozzato G, et al. Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas. Blood 1998; 91: Kaplanski G, Maisonobe T, Marin V, et al. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in the pathogenesis of severe forms of vasculitis due to hepatitis C-associated mixed cryoglobulinemia. J Hepatol 2005; 42: The study underlines the pathogenetic and therapeutic relevance of high serum levels of vascular cell adhesion molecule-1 in patients with HCV-positive cryoglobulinemic vasculitis compared with HCV-infected patients without cryoglobulinemic syndrome. 34 Fabris M, De Marchi G, Sacco S, De Vita S. Fibronectin gene polymorphisms influence type ii mixed cryoglobulinemia clinical manifestations [abstract]. Ann Rheum Dis 2005; 64 (Suppl iii): Park KJ, Choi SH, Choi DH, et al. Hepatitis C virus NS5A protein modulates c-jun N-terminal kinase through interaction with TNF receptor-associated factor 2. J Biol Chem 2003; 278: Hosui A, Ohkawa K, Ishida H, et al. Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferongamma stimuli. J Biol Chem 2003; 278: Zignego AL, Ferri C, Giannelli F, et al. Prevalence of BCL-2 rearrangement in hepatitis C virus-related mixed cryoglobulinemia with or without complicating B-cell lymphoma. Ann Intern Med 2002; 137: Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science 1998; 282: Machida K, Cheng KT, Sung VM, et al. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 2004; 23: This is an excellent molecular laboratory study supporting the oncogenetic potential of HCV infection with regards to both liver carcinoma and B-cell lymphomas. These findings are particularly relevant in the field of RNA-virus related oncogenesis. 40 Antonelli A, Ferri C, Fallahi P, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM 2004; 97: This study confirms the suggested role of HCV in thyroid dysfunction and cancer in patients with cryoglobulinemic vasculitis. 41 Ferri C, Fallahi P, Ghinoi A, et al. Thyroid involvement in HCV-related cryoglobulinemic vasculitis. Ann Rheum Dis 2005; 64 (Suppl III): Fujino Y, Tamakoshi A, Hoshiyama Y, et al. Prospective study of transfusion history and thyroid cancer incidence among females in Japan. Int J Cancer 2004; 20: This study supports the possible role of HCV in thyroid cancer on the basis of epidemiological observations. 43 Duberg AS, Nordstrom M, Torner A, et al. Non-Hodgkin s lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology 2005; 41: Rieu V, Cohen P, Andre MH, et al. Characteristics and outcome of 49 patients with symptomatic cryoglobulinaemia. Rheumatology (Oxford) 2002; 41:

9 62 Vasculitis syndromes 45 Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum 1999; 42: Hermida Lazcano I, Mendez LS, Santos JS. Mixed cryoglobulinemia with renal failure, cutaneous vasculitis and peritonitis due to Brucella melitensis. J Infect 2005; 10 June [Epub ahead of print]. 47 Tagle M, Barriga JA, Gutierrez S, et al. Relapsing viral hepatitis type A complicated with renal failure. Rev Gastroenterol Peru 2004; 24: Castillo JR, Kirchner E, Farver C, Calabrese LH. Cryoglobulinemic vasculitis and lymphocytic interstitial pneumonitis in a person with HIV infection. AIDS Read 2005; 15: Granel B, Serratrice J, Morange PE, et al. Cryoglobulinemia vasculitis following intravesical instillations of bacillus Calmette-Guerin. Clin Exp Rheumatol 2004; 22: Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore) 2001; 80: Casato M, Lilli D, Donato G. Occult hepatitis C virus infection in type II mixed cryoglobulinaemia. J Viral Hepat 2003; 10: Castillo I, Pardo M, Bartolomé J, et al. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver function tests is unknown. J Infect Dis 2004; 189:7 14. An important study focusing on the subset of patients with suspected HCV-related diseases but without HCV serological markers. In these patients virological evaluation of liver biopsy can be decisive for the correct diagnosis. 53 Carreno V, Castillo I, Bartolomé J, et al. Comparison of hepatitis C virusrna detection in plasma, whole blood and peripheral blood mononuclear cells of patients with occult hepatitis C virus infection. J Clin Virol 2004; 31: This study reinforces the relevance of occult HCV infection and the major role of liver biopsy to detect viral infection compared with peripheral lymphocyte analysis. 54 Fadda P, La Civita P, Zignego AL, Ferri C. Hepatitis C virus infection and arthritis: a clinico-serological investigation of arthritis in patients with or without cryoglobulinemic syndrome. Reumatismo 2002; 54: Wener MH, Hutchinson K, Morishima C, Gretch DR. Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis-Rheum 2004; 50: This interesting study suggests the usefulness of anti-ccp determination for a correct diagnosis of rheumatoid arthritis in HCV-positive patients with and without rheumatic disorders, including mixed cryoglobulinemia. 56 Seo JH, Ryan HF, Claussen GC, et al. Sensory neuropathy in vasculitis: a clinical, pathologic, and electrophysiologic study. Neurology 2004; 63: Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests. J Rheumatol 2005; 32: This excellent study demonstrated the high rate of impaired cognitive function and inflammatory central nervous system involvement in a large series of mixed cryoglobulinemia patients. 58 Morgello S. The nervous system and hepatitis C virus. Semin Liver Dis 2005; 25: Uchiyama Tanaka Y, Mori Y, Kishimoto N, et al. Membranous glomerulonephritis associated with hepatitis C virus infection: case report and literature review. Clin Nephrol 2004; 61: The authors report an interesting observation of renal viral inclusions in cryoglobulinemic glomerulonephritis, along with a good review of the literature. 60 Antonelli A, Ferri C, Fallahi P, et al. Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford) 2004; 43: The high risk of developing type 2 diabetes is demonstrated in a large series of cryoglobulinemic patients. 61 Ferri C, Bertozzi MA, Zignego AL. Erectile dysfunction and HCV infection. JAMA 2002; 14: Monteverde A, Rivano MT, Allegra GC, et al. Essential mixed cryoglobulinemia, type II: a manifestation of low malignant lymphoma? Clinicalmorphological study of 12 cases with special reference to immunohistochemical findings in liver frozen sections. Acta Haematol 1988; 79: Monti G, Pioltelli P, Saccardo F, et al. Incidence and characteristics of non- Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005; 165: This multicenter study demonstrated the increased incidence and the clinicopathological features of B-cell lymphomas complicating HCV-related cryoglobulinemic vasculitis. The relative risk of developing non-hodgkin s lymphoma is about 35 times higher compared with the general population. 64 Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 2005; 105: This excellent study further supports the previous description of a frequent association between splenic lymphoma with villous lymphocytes, cryoglobulinemic vasculitis, and HCV infection. 65 Ferri C, Longombardo G, La Civita L, et al. Hepatitis C virus as common cause of mixed cryoglobulinemia and chronic liver disease. J Intern Med 1994; 236: Lamprecht P, Gutzeit O, Csernok E, et al. Prevalence of ANCA in mixed cryoglobulinemia and chronic hepatitis C virus infection. Clin Exp Rheumatol 2003; 21 (6 Suppl 32):S89 S Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogren s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: Ramos-Casals M, Garca-Carrasco M, Cervera R, et al. Hepatitis c virus infection mimicking primary Sjogren s syndrome: a clinical and immunologic description of 35 cases. Medicine (Baltimore) 2001; 80: Ioannidis JPA. Vassiliou VA, Moutsopoulos HM. Long term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren s syndrome. Arth Rheum 2002; 46: Vasil ev VI, Probatova NA, Varlamova EIu, et al. Prognostic implications of mixed monoclonal cryoglobulinemia in Sjogren s disease. Ter Arkh 2004; 76: This is an interesting follow-up study reporting the worse prognosis of Sjogren s disease associated with mixed cryoglobulinemia. The authors did not correlate this important finding with the possible HCV exposure. 71 Pillemer SR, Smith J, Fox P, Bowman SJ. Outcome measures for Sjogren s syndrome, april 10 11, Bethesda, Maryland, USA. J Rheumatol 2004; 31: Ramos-Casals M, Brito-Zeron P, Yague J, et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren s syndrome. Rheumatology (Oxford) 2005; 44: Ramos-Casals M, De Vita S, Tzioufas A. Hepatitis C virus, Sjogren s syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer. Autoimmun Rev 2005; 4: Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine 2005; 84: The authors suggest the term of Sjogren s syndrome secondary to HCV for a specific patient subset characterized by HCV infection and sicca syndrome. A careful analysis of this subset shows a peculiar combination of low rate of ENA autoantibodies, mixed cryoglobulinemia, hypocomplementemia, and frequent vasculitic manifestations. 75 Perlemuter G, Cacoub P, Sbai A, et al. Hepatitis C virus infection in systemic lupus erythematosus: a case-control study. J Rheumatol 2003; 30: Buskila D. Hepatitis C-associated arthritis. Curr Opin Rheumatol 2000; 12: Invernizzi F, Galli M, Serino G, et al. Secondary and essential cryoglobulinemias: frequency, nosological classification, and long-term follow-up. Acta Haematol 1983; 70: Sene D, Ghillani-Dalbin P, Thibault V, et al. Long term course of mixed cryoglobulinemia in patients infected with hepatitis C virus. Rheumatology 2004; 31: Ferri C, Giuggioli D, Cazzato M, et al. HCV-related cryoglobulinemic vasculitis: an update on its etiopathogenesis and therapeutic strategies. Clin Exp Rheumatol 2003; 21 (Suppl 32):S78 S Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to a-interferon therapy. Cancer 1996; 77: Giannelli F, Moscarella S, Giannini C, et al. Effect of antiviral treatment in patients with chronic HCV infection and t[14;18) translocation. Blood 2003; 102: Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis 2004; 43: The authors describe the therapeutic usefulness of antiviral treatment in a large series of cryoglobulinemic glomerulonephritis patients. 83 Cacoub P, Saadoun D, Limal N, et al. PEGylated Interferon Alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2005; 52: The study confirms the efficacy of antiviral treatment in nine patients with HCVassociated cryoglobulinemic vasculitis.