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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.

Objective: To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjögren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma., Methods: Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma., Results: Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma., Conclusion: Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).

Objective: To establish if spondyloarthritis (SpA) and vitiligo occur together more frequently than by chance., Methods: All consecutive patients with SpA seen in a 6 month period were evaluated for vitiligo by an experienced dermatologist. The control group included the 2 consecutive patients without SpA seen after each patient with SpA., Results: Two hundred thirty-four patients with SpA (131 men, 103 women; mean age 59 +/- 18.3 yrs) were seen in the study period. Of these, 43 had ankylosing spondylitis (AS), 112 psoriatic arthritis (PsA), 14 SpA associated with inflammatory bowel disease, 64 undifferentiated SpA, and one reactive arthritis. The 468 control patients (360 women, 108 men; mean age 68.5 +/- 2 yrs) had various degenerative and inflammatory rheumatic diseases. Eight (3.4%) patients out of 234 with SpA had type A vitiligo. In the control group, 5 (1.06%) out of 468 had type A vitiligo. The difference was statistically significant (p < 0.05). Of the 8 patients with coexisting vitiligo and SpA, 4 had PsA, 2 primary AS, one AS associated with Crohn's disease, and one undifferentiated SpA. Of the 5 patients with vitiligo in the control group, one had rheumatoid arthritis, one S ogren's syndrome, one palindromic rheumatism, one crystal arthropathy, and one osteoarthritis., Conclusion: Our results suggest that vitiligo and SpA do not coexist by chance and that vitiligo should be included in the list of diseases associated with SpA.

Lower urinary tract involvement is an uncommon manifestation of systemic sclerosis; however, it may represent a troublesome disturbance affecting the quality of life in systemic sclerosis patients. Here we report the case of a middle-aged woman with a 5-year history of systemic sclerosis, who developed severe and progressive urinary bladder sclerosis. This report is particularly interesting because of the severity of the bladder involvement, which required surgical treatment.

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, Sjögren'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 postischaemic 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 < 0.001). Moreover, among SSc patients a lower (p < 0.05) vasodilatory response to Ach compared with ischaemia and SNP was recorded., Conclusions: These data confirm a reduction of skin digital vasodilatory reserve in SSc patients and suggest a defect of both endothelial dependent arteriolar relaxation and wall compliance in the pathogenesis of this dysfunction.

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.

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.

Some lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been proposed as causative agents of B cell non-Hodgkin's lymphoma (NHL). More recently, the presence of hepatitis C virus (HCV), which is both a hepatotropic and lymphotropic virus, has been reported in one third of B cell NHL patients. The aim of this study was to investigate in a series of B cell NHL the prevalence of three lymphotropic viruses, i.e. EBV, HHV-6 and HCV, in peripheral blood mononuclear cells (PBMC). Eighteen unselected B cell NHL patients (10 men, 8 women; mean age 62 +/- 12 years, range 31-77 years; mean disease duration 1.8 +/- 1.4 years) and 40 age- and sex-matched healthy controls were included in the study. In all cases, an acquired-immunodeficiency-syndrome-related lymphoma was excluded. By means of the polymerase chain reaction technique, EBV DNA, HHV-6 DNA and HCV RNA were detected in PBMC. HCV genomic sequences were significantly more frequent in PBMC of NHL patients than in controls (33 vs. 2.5%; p < 0.01); on the other hand, in the same two groups EBV DNA (39 vs. 60%; p = not significant) and HHV-6 DNA (22 vs. 32%; p = not significant) were present in a comparable percentage of individuals in the same two groups. The infection of PBMC by HCV alone was present in the majority (5 of 6) of HCV-positive NHL. These data support the implication of HCV infection in a statistically significant number of B cell NHL, whereas a possible co-operation between HCV and other well-known lymphotropic viruses seems to be excluded.

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.

An association between hepatotropic viruses, chiefly hepatitis C virus (HCV), occasionally hepatitis B virus (HBV), and mixed cryoglobulinemia has been widely reported. Alpha-interferon (IFN-alpha) has usefully been employed in the treatment of mixed cryoglobulinemia, particularly for liver and renal involvement. IFN-alpha treatment may be associated with neurological complications, including peripheral neuropathy. We describe an HBV positive patient with mixed cryoglobulinemia with recurrent purpura, mild sensory peripheral neuropathy, and active hepatitis treated with IFN-alpha. Rapid improvement of the purpura, liver enzymes, and cryocrit, and disappearance of serum HBV DNA were observed after a 4 week treatment period. However, concomitant worsening of the neuropathy prompted us to discontinue IFN-alpha. Although in this case, a positive effect of IFN-alpha on the clinico-serological and virological variables was confirmed, due to the possible exacerbation of neurological manifestations, a careful patient evaluation is necessary before starting IFN-alpha in patients with mixed cryoglobulinemia.

Gaucher s disease is an autosomal recessive lysosomal storage disease characterized by the specific deficiency of glucocerebrosidase that leads to accumulation of insoluble glucocerebroside in the reticuloendothelial system, particularly the bone marrow, liver, spleen and lymph nodes. Direct scintigraphic visualization of lipid deposits in Gaucher s disease has recently been described, based on the use of the lipid-soluble xenon-133. We report here on the use of the lipophilic cationic complex technetium-99m sestamibi (99mTc-MIBI), employed as an indicator of increased cellular density and metabolic activity, to evaluate Gaucher cell infiltrates in the bone marrow; 99mTc-hexametazime (99mTc-HMPAO) was also employed, as a pure indicator of lipidic infiltration in the bone marrow. A 67-year-old patient with known type 1 Gaucher s disease presented with a painful left hip and knee and difficulty in gait subsequent to traumatic fracture of the left femoral neck that had required implant of a fixation screw-plaque. Bone scan with 99mTc-methylene diphosphonate revealed reduced uptake at the distal metaphyseal-epiphyseal femoral region. In addition, whole-body maps and spot-view acquisitions of the thighs and legs were recorded at both 30 min and 2.5 h after the injection of 99mTc-MIBI: the scintigraphic pattern clearly showed increased uptake at several sites involved by Gaucher deposits in the bone marrow (both knees, with variable intensity in different areas), matching the bone changes detected by conventional x-ray. The target to non-target ratios slowly decreased with time, from an average value of 2.25 in the early scan to an average value of 2 in the delayed scan. The lipid-soluble agent 99mTc-HMPAO exhibited a superimposable scintigraphic pattern of accumulation at the involved sites, though with lower target to non-target ratios (1.27-1.48). The results obtained in this patient suggest a potential role of 99mTc-MIBI in the scintigraphic evaluation of Gaucher s lipid deposits in the bone marrow. If the results are confirmed in other patients, this radiopharmaceutical would offer clear advantages over 133Xe because of its wider availability and greater practicality (i.v. administration of 99mTc-MIBI versus inhalation of 133Xe, and use of a single gamma camera instead of two as with 133Xe).

Bone involvement can represent the inaugural symptom of Gaucher's disease (GD). Here, we report the case of a 68-year old man diagnosed as having GD since 1963. In June 1994 the patient was referred to our Rheumatology Unit because of a long-lasting coxalgia on the left hip and progressive walking impairment following traumatic fracture of the left femur. Multicystic osseous changes at standard X-ray and hyper-gamma-globulinemia with an elevated ESR (122 mm, 1st hour) suggested the diagnosis of either osteonecrosis of the femoral head or multiple myeloma. On bone marrow biopsy examination, Gaucher's cell infiltrates were detected and an increased uptake in the distal left femur and proximal tibia were demonstrated by lipophilic tracer scan (99mTc-Sestamibi). Subsequently, the patient suffered another femoral fracture at a site of Gaucher's infiltrates previously documented by bone scan. We conclude that in patients with GD, 99mTc-Sestamibi bone scan can selectively evaluate the presence of bone lipid deposits, and could indirectly differentiate this bone condition from other serious skeletal complications of the disease.

Hepatitis C virus (HCV), a hepatotropic and lymphotropic virus, is the major causative agent of nonA-nonB 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/III 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 investigate the possible role of HCV variants in the pathogenesis of mixed cryoglobulinemia., Setting: Medical service (rheumatology and hepatology units) of urban, university-affiliated teaching hospitals., Design: Analysis of viral genotypes in a cohort of patients with hepatitis C virus (HCV) infection and mixed cryoglobulinemia., Patients: 90 unselected HCV-positive (anti-HCV antibody-positive and HCV RNA-positive) patients consecutively recruited at routine ambulatory visits: 29 with and 61 without (control group) mixed cryoglobulinemia., Measurements: Clinical and histologic data; HCV RNA detection in serum and peripheral blood mononuclear cells by polymerase chain reaction (PCR); HCV genotype determination by two methods based on genotype-specific primer PCR and genotype-specific probe hybridization, respectively., Results: Persistent aminotransferase increases were found in 55% of patients with mixed cryoglobulinemia. Peripheral blood mononuclear cells were infected in 80% of cases. In serum samples, HCV genotype 2a/III was detected with a higher prevalence in patients with mixed cryoglobulinemia than in controls (41% compared with 15%). The overall prevalence of genotype 2a/III in mixed cryoglobulinemia increased to 52% when findings in peripheral blood mononuclear cells were also considered. Among patients with mixed cryoglobulinemia, this genotype was more frequent in those without clinical and biochemical signs of liver disease (85%) or with serum autoantibodies (75%)., Conclusions: Mixed cryoglobulinemia may be related, at least in part, to the HCV genotype infecting the host.

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.

The principal therapeutic procedures and when they are clinically indicated in the management of essential mixed cryoglobulinemia (EMC) have been the subject of much debate. This paper reviews current knowledge and our experience in the treatment of this complex disease. It is generally agreed that patients with purpura, the primary symptom of EMC, should avoid long periods of sitting or standing in the same position. Non-steroidal antiinflammatory drugs can be used for the management of arthralgias and/ or arthritis. Low dose steroids (0.5-0.3 mg/kg/die) are usually sufficient to control the purpura, arthralgias, arthritis and weakness, while larger doses (0.5-1.5 mg/kg/die) are needed to treat the renal involvement, peripheral neuropathy and serositis. Since the discovery of the association between EMC and viral infections, the appropriateness of cytotoxic drugs has been re-evaluated and they are no longer used. With the low antigen content diet, a regimen designed to restore a saturated mononuclear phagocytic system, good results have been obtained in the treatment of purpura, arthralgias, weakness and peripheral neuropathy. Furthermore, this dietary regimen may play a steroid sparing role. Plasma exchange is widely used in the management of severe renal involvement, hyperviscosity syndrome, sensory motor neuropathy and liver involvement in EMC.

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.