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Mixed cryoglobulinaemia (MC) is a systemic vasculitis, secondary to the deposition in small and medium-sized blood vessels of circulating immune complexes, mainly the cryoglobulins, and complement. MC is characterised by a typical clinical triad (purpura, weakness, arthralgias) and by one or more organ involvement: chronic hepatitis, glomerulonephritis, peripheral neuropathy, skin ulcers and diffuse vasculitis. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Hepatitis C virus (HCV) infection has been found in the majority of patients with MC; the frequency of HCV markers (91%) was significantly higher than other rheumatic diseases (6.4%), namely systemic lupus, Sjùgren's syndrome, rheumatoid arthritis and systemic sclerosis, or healthy controls (1.2%). The HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production. In a similar way, HCV infection may also be involved in the pathogenesis of other autoimmune (glomerulonephritis, thyroiditis, lung fibrosis, autoimmune hepatitis, porphyria cutanea tarda) and lymphoproliferative disorders (monoclonal gammopathies, B-cell lymphomas). MC shares numerous clinico-serological and pathological features with the above disorders. HCV seems to be their common etiological agent; however, a variable combination of unknown co-factors (infectious, genetic, environmental) should be determinant for the appearance of different clinical patterns.

OBJECTIVES—To investigate the skin vasodilatory response to iontophoretically applied acetylcholine (Ach), an endothelium dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium independent vasodilator, in patients with systemic sclerosis (SSc). METHODS—Eleven SSc patients were preliminarily studied (10 females, mean age 40.5; mean disease duration 6.5 years), and 16 age and sex matched control subjects. By means of laser Doppler flowmetry skin blood flow was evaluated at third finger, at baseline, and after post-ischaemic hyperaemia test and during iontophoretically transcutaneous application of 1% solution of Ach and SNP. RESULTS—No significant differences in basal skin blood flow were detected between SSc patients and controls. Cutaneous vasodilatory response to ischaemia, Ach, and SNP was significantly less pronounced in SSc patients compared with controls (p

Treatment with calcium antagonists has been shown to be beneficial in patients with primary and secondary Raynaud’s phenomenon. A double-blind placebo-controlled crossover trial was performed to assess the efficacy of amlodipine, a new long-acting calcium antagonist, in patients with Raynaud’s phenomenon without underlying disease. 20 of the 24 patients enrolled (20 women and 4 men, mean age 45 years) completed the trial. The number of episodes of Raynaud’s phenomenon per week and the severity of discomfort significantly improved during amlodipine (p < 0.0001 and p < 0.0004, respectively) but not placebo treatment. Perfusion-pressure index, evaluated with Doppler sonography using a postischaemia reactive hyperaemia test, significantly improved (p < 0.04) after treatment with amlodipine but not placebo. These results indicate that amlodipine is a useful treatment for primary and suspected secondary Raynaud’s phenomenon, at least in the short term.

Summary Hepatitis C virus (HCV), a hepatotropic and lymphotropic virus, is the major causative agent of nonAnonB chronic hepatitis; moreover, it is frequently associated with benign and malignant lymphoproliferative disorders such as mixed cryoglobulinaemia and B-cell non-Hodgkin's lymphoma (NHL). We investigated the clinical and virological features of B-cell NHL complicating chronic hepatitis C in a series of 10 patients (M/F 1/9; mean age 63 + 6SD years). The malignancy appeared after median 8 + 4SD years from onset and was low-grade in six patients, intermediate in three, and high-grade in one. 'One-tube nested' PCR detected serum HCV RNA and viral ongoing replication in both fresh and cultured peripheral lymphocytes in all ten. Analysis of HCV genotypes showed a relatively higher prevalence of 2a/lll type compared with unselected chronic hepatitis C (50% vs. 15%). In one patient, HCV RNA was also found in the neoplastic bone marrow and lymph-node specimens. B-cell NHL can complicate chronic hepatitis C and affect the overall prognosis of the disease. The increasing frequency of chronic hepatitis C worldwide suggests that the actual prevalence of this complication may be underestimated. Careful clinical work-up at diagnosis and during follow-up is particularly recommendable.

Objective: To compare the clinico-serological features of arthritis from two HCV+ patient groups characterised by mixed cryoglobulinemia (MC) or chronic hepatitis (CH). Methods: We retrospectively studied 157 MC patients (119 females, mean age 64.8 yrs, range 36-88) and 155 CH patients (103 females, mean age 58.8 yrs, range 30-81). Patients with HBV and/or HIV co-infections and a follow-up shorter than 1 year were excluded. MC was classified according to standard criteria, while CH classification was based on Desmet’s criteria. Results: No differences in epidemiology were demonstrated between the two series of patients. Although significantly prevalent in MC patients, extra-hepatic manifestations including nephropathy, neuropathy, pneumopathy, mixed cryoglobulins, RF positivity and hypocomplementemia were detected in both patient groups. Arthritis was present in 23 CH (15%) and 12 MC (8%) patients. A symmetrical polyarthritis was observed in 87% of 23 CH patients, while cryoglobulinemic arthritis was invariably asymmetrical and pauciarticular. Unlike MC patients, who had a constantly nonerosive arthritis, in 7/23 CH patients arthritis was erosive. Steroids and/or hydroxycloroquine or D-penicillamine were safe and useful in controlling the arthritis over the short-medium time, although clinical response was more evident in MC patients. Instead, in 5/23 CH and 3/12 MC patients, interferon-alpha treatment was able to trigger or exacerbate the arthritis despite a good control of liver function. Conclusions: HCV infection seems to be, possibly in genetically predisposed patients, responsible for arthritis at times similar to rheumatoid arthritis. In these patients a careful assessment of the interferon-alpha treatment is mandatory owing to the potential ‘arthritogenic effect’ due to its immunoregulatory properties.

The effects of interferon-alpha (IFN-alpha) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-alpha therapy (2 x 10(6) IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P < .02) and serum transaminases (P < .005) during IFN-alpha treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P < .04) during IFN- alpha therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-alpha discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91% (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN- alpha therapy. Thus, IFN-alpha could be considered as treatment for MC in patients with HCV seropositivity.

To compare the clinico-serological features of arthritis from two HCV+ patient groups characterized by mixed cryoglobulinemia (MC) or chronic hepatitis (CH).We retrospectively studied 157 MC patients (119 females, mean age 64.8 yrs, range 36-88) and 155 CH patients (103 females, mean age 58.8 yrs, range 30-81). Patients with HBV and/or HIV co-infections and a follow-up shorter than 1 year were excluded. MC was classified according to standard criteria, while CH classification was based on Desmet's criteria.No differences in epidemiology were demonstrated between the two series of patients. Although significantly prevalent in MC patients, extra-hepatic manifestations including nephropathy, neuropathy, pneumopathy, mixed cryoglobulins, RF positivity and hypocomplementemia were detected in both patient groups. Arthritis was present in 23 CH (15%) and 12 MC (8%) patients. A symmetrical polyarthritis was observed in 87% of 23 CH patients, while cryoglobulinemic arthritis was invariably asymmetrical and pauciarticular. Unlike MC patients, who had a constantly non-erosive arthritis, in 7/23 CH patients arthritis was erosive. Steroids and/or hydroxycloroquine or D-penicillamine were safe and useful in controlling the arthritis over the short-medium time, although clinical response was more evident in MC patients. Instead, in 5/23 CH and 3/12 MC patients, interferon-alpha treatment was able to trigger or exacerbate the arthritis despite a good control of liver function.HCV infection seems to be, possibly in genetically predisposed patients, responsible for arthritis at times similar to rheumatoid arthritis. In these patients a careful assessment of the interferon-alpha treatment is mandatory owing to the potential "arthritogenic effect" due to its immunoregulatory properties.

Background Raynaud’s phenomenon (RP) is a microcirculatory disorder characterised by deficient endothelial activity. Such endothelial dysfunction should be responsible for reduced release of NO, a potent vasodilatory agent. Since the cell function is dependent on energy production, it is though deficient endothelial activity could be due to the loss of energy production probably secondary to a low availability of Carnitine, an important cell metabolic carrier. Objectives To conduct a preliminary evaluation of the serum Carnitine concentrations in primary RP patients (pRP pts.) compared to age- and sex-matched controls. Methods After verbal consent, 17 consecutive pRP pts (16 female, mean age 32.1 ± 11.3 yrs) and ten control subjects (9 female, mean age 34 ± 11 yrs) were enrolled for this study. Patients had to have a RP history no longer than 5 years. After acclimatisation, each subject underwent a venous blood drawing from same vessel at baseline and after a 5-minute cold-water test. All blood samples were stored ?20°C. Then, Carnitine was measured in collected sera by enzymatic assay (SIGMA-TAU pharmaceuticals). T-test for paired data was used for statistical analysis. Results Table 1 showed the mean values of serum Carnitine concentrations in two studied groups. After test, serum Carnitine concentration increased in 12/17 pRP patients and lowered in the remainders. Contrary, in the control group circulating Carnitine increased significantly after provocative test. Conclusion Lower circulating Carnitine titres in our pRP pts could be associated with diminished availability of Carnitine in endothelial cells and consequently with their impaired activity. Although this study is preliminary, our results suggest Carnitine supplementation for promotion of endothelial activity in pRP pts may be worth investigating, particularly in RP subjects unresponsive to conventional treatments.

An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses, chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV genomic sequences or HCV-related viral proteins in the serum, purified cryoglobulins, peripheral blood mononuclear cells and into several tissues has suggested an important triggering role for HCV in MC patients. However, only few reports investigated the presence of HCV in cutaneous vasculitis and its potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC female patients (aged from 40 to 80 years) were carried out for virological and histopathological evaluation. A leukocytoclastic vasculitis pattern was found in 4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases biopsy specimens were sufficient for immunohistochemical and direct immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) immune-complexes. In the same skin specimen APAAP and DIF findings were compared with the presence/ absence of HCV genomic sequences (PCR technique). In 1 MC patient, the detection of HCV-RNA was associated to a prevalent CD8 + T suppressor pattern with a perivascular and subjunctional distribution as well as an intense expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules on basal keratinocytes, endothelial cells and perivascular infiltrate. These findings suggest a marked inflammatory activation that spreads from endothelial cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens the scanty immunopathological staining could indicate a residual activity due to the previous inflammatory event triggered by cryoglobulins. The deposition of circulating HCV-containing immune complexes (CIC) in the skin could be the initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could spread from the vascular bed to the perivascular tissue and then could be very rapidly eliminated. If confirmed in larger patients' series these findings could definitely demonstrate a direct role of HCV in the pathogenesis of cryoglobulinemic vasculitis.

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients): mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high-resolution computed tomography. The presence of parenchymal radiotracer uptake on 67Ga scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders.

Oncogenesis is a multifactorial process in which environmental, genetic and infectious factors are variably involved. A possible role of specific viruses has been suggested in at least 15% of human cancers. Hepatitis C virus (HCV), which is both hepato- and lymphotropic, is responsible for various liver disorders, i.e. chronic hepatitis, cirrhosis and hepatocelluar carcinoma, as well as for a constellation of extrahepatic immune-mediated manifestations, among which is mixed cryoglobulinaemia. This is a systemic disorder secondary to a chronic, benign B-lymphocyte proliferation, which in some subjects may evolve to a malignant non-Hodgkin's lymphoma (NHL). Interestingly, recent studies reported the appearance of malignant B-cell neoplasias in patients with type C chronic hepatitis; moreover, in a significant number (from 22% to 50%) of 'idiopathic' NHLs, the presence of HCV infection has been demonstrated. The presence of a geographical etherogeneity in the prevalence of HCV-positive NHL suggests that other co-factors, i.e. genetic and environmental, could be involved in the lymphomagenesis. HCV may exert its oncogenic potential in two different directions, leading to liver cancer or B-cell lymphoma.

We investigated the pathogenetic relevance of hepatitis C virus (HCV) infection in mixed cryoglobulinemia (MC) with or without complicating B-cell Non-Hodgkin's lymphoma (NHL) in comparison with other immunological and lymphoproliferative disorders. The following groups of patients were studied: A) 25 patients with MC in 7 cases evolved into B-cell NHL; B) 25 healthy subjects; C) 22 patients with different systemic immune diseases; D) 24 patients with chronic HCV infection without MC; E) 25 patients with B-cell idiopathic NHL. Methods used included: i) Polymerase chain reaction (PCR) for HCV RNA detection in serum and peripheral blood mononuclear cells (PBMC) (uncultured or mitogen-stimulated); ii) Branched DNA (b-DNA) for HCV RNA quantification; iii) HCV genotyping by genotype-specific primers localized in the core region and by hybridization of amplification products of the 5' untranslated region (5'UTR), obtained with universal primers, using genotype-specific probes. Serum anti-HCV and HCV RNA were detected in 88% and 73% of MC patients, respectively, and in a significantly lower percentage of healthy controls and patients with autoimmune diseases. HCV RNA concentration was significantly lower in supernatants than in corresponding whole sera (p < 0.001). Plus-strand HCV RNA was detected in 81% of peripheral blood mononuclear cell (PBMC) samples and minus-strand in the majority of fresh or mitogen stimulated cells. All MC patients with NHL had HCV RNA sequences in PBMC. HCV genotype 2a/III was detected in MC patients with a prevalence that was significantly higher than in HCV infected patients without MC. Surprisingly, HCV markers (anti-HCV and/or HCV RNA) were found in 32% of patients with idiopathic NHL. These data suggest that HCV infection is involved in the pathogenesis of MC through both direct participation in the immune complex related vasculitis and by triggering the lymphoproliferative disorder underlying the disease. This latter disorder seems to be related to HCV lymphotropism which could also be responsible for the evolution of MC to malignant lymphoma. This study also suggests that HCV infection may be involved in the pathogenesis of idiopathic B-cell NHL through a similar pathogenetic mechanism.

The term ‘cryoglobulin’ was introduced to define a group of proteins which have the common property of forming a reversible precipitate or gel in the cold [1]. Three groups of cryoglobulins have been identified. Type I cryoglobulins are monoclonal, the most common one being immunoglobulin M (IgM), a protein associated with immunoprolifera-tive disorders, such as Waldenstrom’s macroglobulinemia, lymphopro-liferative disorders and multiple myeloma.

In order to evaluate the nature and prevalence of audiovestibular disturbances in mixed cryoglobulinaemia (MC), 32 consecutive MC patients were studied by a wide audiological and vestibular examination. Pure tone audiometry, impedance audiometry, brainstem response audiometry and vestibular function were performed. Patients with a previous history of ear damage due to other well-known agents were excluded from the study. In MC patients we found a rather frequent audiovestibular involvement (34.3%). Bilateral sensorineural hearing loss was found in seven MC patients (22%) and altered vestibular function test values in other seven subjects (22%). Moreover, anamnestic and clinical data revealed a high incidence of benign positional paroxysmal vertigo in our MC series. We can suppose that immune complex-mediated microvascular involvement of the labyrinthine vessels may be responsible for inner ear damage in MC. Thus, audiovestibular disturbances may be included among various organ involvement of the MC.

Hepatitis C virus (HCV) infection has been found in the majority of patients with mixed cryoglobulinemia (MC) in studies conducted in different countries. In our series of 110 MC patients the frequency of HCV markers was significantly high (91%) compared with other rheumatic diseases (6.4%) and with healthy Italian controls (1.2%). Moreover, HCV RNA was detected in 81% of the peripheral lymphocytes from MC patients. Comparable percentages of HCV infection were detectable in other disorders, i.e. porphyria cutanea tarda (77%) and autoimmune hepatitis type 1 (77%). The HCV infection of peripheral lymphocytes suggests that this virus could be the triggering factor for the lymphoproliferation underlying MC. In a number of patients with MC the evolution from a benign lymphoproliferation to frank B-cell lymphoma was observed. In these subjects HCV RNA in the sera and in fresh and cultured peripheral lymphocytes was constantly detected. The same phenomenon has been observed in patients with long-lasting type C chronic hepatitis. Interestingly, HCV infection has also been recorded in 32% of idiopathic B-cell non-Hodgkin's lymphomas. Taken together, the above findings suggest that HCV can cause benign B-cell proliferation with the consequent production of various autoantibodies, including rheumatoid factor and mixed cryoglobulins. These serological abnormalities characterise different clinical disorders, including the appearance of lymphoma in a not negligible number of individuals.

Objectives. Mixed cryoglobulinaemia (MC) and autoimmune chronic hepatitis (AI-CH) are frequently associated with hepatitis C virus (HCV) chronic infection. Because HCV represents a possible common aetiological factor, the aim of the present study is to investigate the clinico-serological alterations of both MC and AI-CH and to verify a possible overlap between these disorders. Setting. Patients from three tertiary referral centres. Subjects. Two Italian series of 88 MC patients and 30 AI-CH type 1 were studied. Results. MC and AI-CH share several clinico-sero-logical features. The patients' mean age (MC vs. AI-CH: 60 ± 9 vs. 57 ± 13 years), disease duration (10.5 ± 5 vs. 9.6 ± 6 years), and female/male ratio (3.4 vs. 3.3) were very similar in the two series. Typical hallmarks of MC, i.e. purpura, arthralgias, and weakness, circulating mixed cryoglobulins with rheumatoid factor activity, and hypocomplement-emia were also recorded in a significant number of AI-CH patients. Similarly, chronic active hepatitis was found in 68% of MC patients and its histological and serological alterations were comparable with those of AI-CH; moreover, amongst various auto-antibodies, antinuclear antibodies and/or anti-smooth-muscle antibodies were detected in half of the cases of MC. Anti-HCV antibodies, detected by second-generation Chiron elisa and riba, were present in a high percentage of both MC and AI-CH (94 vs. 80%), and frequently associated with HCV viraemia (86 vs. 77%). Finally, anti-GOR, the HCV-related autoantibodies, were found in half cases of MC and AI-CH. Conclusions. On the whole, these data suggest that HCV in combination with other infectious and environmental and genetic factors can trigger a complex immunological disorder with different clinical patterns.

Seroimmunological alterations, including antibodies and/or cryoglobulins, are common in infective endocarditis (IE)1; however, specific autoimmune disorders, such as cryoglobulinaemic vasculitis (CV) associated with IE have seldom been described.2–5 CV is related to the vascular deposition of circulating immune complexes, mainly cryoglobulins, and complement5,6; in 70–90% of patients with CV a triggering role of hepatitis C virus (HCV) has been suggested.7,8 We report the case of two patients who showed a typical CV with severe neurological involvement as the presenting manifestation of underlying IE. In November 1994 a 63 year old woman presented with fever, purpura, paraesthesias, and pseudoataxic gait. Her past clinical history was unremarkable except for a prosthetic implant of the left hip four years previously. Table 1 shows the main clinicoserological features. Repeated blood cultures were negative. Neurological examination showed abnormal tactile sensation in the arms and legs; mild ideomotor slowing down; shaky movements; and unsteady gait. An electrophysiological study recorded a moderate sensorimotor …

Hepatitis C virus (HCV) infection is frequently found in autoimmune hepatitis and mixed cryoglobulinaemia. In these conditions HCV could be responsible for immuno-mediated organ alterations. The aim of this study was to evaluate the presence of immunological alterations in PCT patients, in which HCV infection has been frequently found. Twenty-three PCT patients were evaluated for clinical and serological alterations, including: chronic hepatitis, other systemic symptoms, serum cryoglobulins and rheumatoid factor (RF), haemolytic complement, serum immunoglobulins, anti-nuclear (ANA), anti-smooth muscle (ASMA), anti-liver-kidney-microso-mal (anti-LKMl), anti-soluble-liver-antigen (SLA), anti-mitochondrial (AMA), anti-GOR antibodies, anti-HCV and HCV RNA. Abnormal serum ALT were present in the majority of cases (20/23, 87%), while liver biopsy revealed a chronic persistent hepatitis or chronic active hepatitis in 15/20 (75%) PCT patients. In a high percentage of subjects (91%) the presence of anti-HCV was detected by ELISA and RIBA II (Chiron, Emeryville CA, USA). In 17/22 (77%) cases the ongoing HCV replication in the serum was demonstrated by the detection of HCV genomes (polymerase chain reaction). The prevalence of both anti-HCV and HCV RNA in PCT was significantly higher if compared to 22 systemic immunological diseases (P< 0.00l) and 47 healthy subjects (P

The effects of interferon-alpha (IFN-alpha) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-alpha therapy (2 x 10(6) IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P.02) and serum transaminases (P.005) during IFN-alpha treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P.04) during IFN-alpha therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-alpha discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91% (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN-alpha therapy. Thus, IFN-alpha could be considered as treatment for MC in patients with HCV seropositivity.

Treatment with calcium antagonists has been shown to be beneficial in patients with primary and secondary Raynaud’s phenomenon. A double-blind placebo-controlled crossover trial was performed to assess the efficacy of amlodipine, a new long-acting calcium antagonist, in patients with Raynaud’s phenomenon without underlying disease. 20 of the 24 patients enrolled (20 women and 4 men, mean age 45 years) completed the trial.

Peripheral neuropathy has been described in different rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic vasculitis, but usually in limited numbers of patients. Nerve injury is more frequently reported in mixed cryoglobulinemia. In earlier studies generally performed in small series of patients, prevalence of peripheral neuropathy varied widely. We evaluated prevalence of peripheral neuropathy in 33 unselected patients with mixed cryoglobulinemia (25 women, 8 men, aged from 45-71 years). Neurologic involvement was detected using a complete clinical and electrophysiologic assessment, including sensory motor conduction velocities, F wave and H reflex. Neurologic examination revealed a neuropathy in 48% of subjects, while electrophysiologic variables were altered in 82%; a percentage similar to that of subjective symptoms (91%). Among electrophysiologic investigations, F wave was altered in 22/33 subjects (67%); therefore, this variable seems to be the most reliable for the detection of neurologic involvement. Cryocrit levels were significantly higher in patients with peripheral neuropathy: abnormal examination (p less than 0.01), sensory motor conduction (p less than 0.04), and F wave alterations (p less than 0.008). In addition, hemorheological abnormalities seem to contribute to the pathogenesis of nerve injury. Our results indicate that peripheral neuropathy, to a variable degree, is present in the majority of patients with mixed cryoglobulinemia, and a complete clinical and electrophysiologic investigation can be useful for an early and correct diagnosis.

To the Editor. —A number of reports have suggested a role for hepatitis C virus (HCV) in a variety of hepatic and extrahepatic disorders (ie, chronic hepatitis, autoimmune hepatitis, porphyria cutanea tarda, Waldenstrom's macroglobulinemia, and mixed cryoglobulinemia).1This latter condition is a "benign" lymphoproliferative disorder that in some subjects can switch over to a malignant B-cell non-Hodgkin's lymphoma (NHL).1Moreover, the demonstration of the HCV lymphotropism2suggested a pathogenetic role for this virus in B-cell expansion underlying some lymphoproliferative disorders. We investigated the prevalence of HCV infection in 24 unselected patients with B-cell NHL (14 men, 10 women; mean±SD age [range], 61±10 years [35 to 74 years]). Diagnosis of B-cell NHL was done by lymph node biopsy specimen evaluated according to the Working Formulation classification3and by immunophenotypic analysis for surface T- and B-lymphocyte markers. All patients were Italian-born heterosexuals and had no history of drug