G. Pasero

Hepatitis C virus infection in patients with non-Hodgkin's lymphoma

Summary. Hepatitis C virus (HCV), which is both a hepatotropic and a lymphotropic virus, has been proposed as a possible causative agent of mixed cryoglobulinaemia. This ‘benign’ lymphoproliferative disorder can switch over to a malignant B‐cell non‐Hodgkins lymphoma (NHL). Therefore HCV infection has been investigated in a series of 50 unselected Italian patients with B‐cell NHL. Antibodies against HCV were found in 30% of NHL and HCV viraemia in 32% of cases. HCV‐related markers were detected in 34% (17/50) of our NHL patients; this prevalence is particularly significant when compared with HCV seropositivity in Hodgkins lymphoma (3%) and healthy controls (1.3%).

THE SYNOVIAL PROSTAGLANDIN SYSTEM IN CHRONIC INFLAMMATORY ARTHRITIS: DIFFERENTIAL EFFECTS OF STEROIDAL AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

1 The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short‐term treatment with 6α‐methyl‐prednisolone (6‐MeP: 4–8mg/day) or indoprofen (1.2g/day), a nonsteroidal anti‐inflammatory agent with proven synovial prostaglandin inhibitory effect. 2 Measurements of prostaglandin E2 (PGE2), thromboxane (TX) B2, 6‐keto‐PGF1α and PGF2α were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin‐layer chromatographic analysis of the extracted immunoreactivity. 3 PGE2 and TXB2 accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds. 4 Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6‐keto‐PGF1α to 90% in the case of PGE2. 5 In contrast, 6‐MeP caused opposite changes on different metabolites originating via the cyclo‐oxygenase pathway. Thus, 6‐keto‐PGF1α concentrations were reduced by 35%, PGF2α concentrations were increased by 30%, while PGE2 and TXB2 were unchanged following 6‐MeP. 6 Although the mechanism(s) underlying the failure of 6‐MeP to reduce synovial PGE2 and TXB2 levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti‐inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side‐effects.

Evaluation of s-adenosylmethionine in primary fibromyalgia: A double-blind crossover study

The effect of S-adenosylmethionine (SAMe) and placebo was evaluated in a short-term crossover study of 17 patients with primary fibromyalgia. Eleven of 17 patients had a significant depressive state as assessed by either the Hamilton Depression Rating Scale or the Scala di Autovalutazione per la Depressione (SAD) rating scale. The number of trigger points plus painful anatomic sites decreased after administration of SAMe (p less than 0.02) but not after placebo treatment. In addition, scores on both the Hamilton and SAD rating scales improved after SAMe administration (p less than 0.05 and p less than 0.005, respectively), whereas they did not significantly change after placebo treatment. In all the patients, there was a good correlation between scores on the Hamilton rating scale and the number of trigger points. Thus, this preliminary study confirms the close relationship between primary fibromyalgia and psychologic disturbances, particularly with regards to a depressive state. SAMe treatment, by improving the depressive state and reducing the number of trigger points, seems to be an effective and safe therapy in the management of primary fibromyalgia.

Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda.

Abstract. 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<0.001). A possible HCV‐induced autoimmunity in PCT was suggested by the presence of the following immunological parameter alterations: anti‐GOR in 13/23 (57%), ANA in 4/23 (17%), ASMA in 18/23 (78%), anti‐LKMI in 1/23 (4%), RFin 23/23 (100%), mixed cryoglobulins in 4/23 (170/0), complement consumption in 10/23 (43%). The high prevalence of HCV infection and various immunological abnormalities suggest that HCV in combination with other factors (genetic, alcohol, etc.) could play a relevant role in the pathogenesis of hepatic and metabolic alterations of PCT.

Sonographic analysis of the ankle in patients with psoriatic arthritis.

Foot involvement is very frequent in patients affected by psoriatic arthritis (PsA). However, evaluation of the painful foot can be problematic, because it is often difficult to distinguish between arthritis, tenosynovitis, and enthesopathy. Plain radiographs can show bone erosion or other features of joint involvement, but give little information about the soft tissues. We therefore studied foot involvement in 31 PsA patients using high resolution sonography, and compared the results with the findings on x-ray and clinical examination. Ultrasound revealed pathological findings in a large proportion of the patients, most of whom exhibited no clinical (pain or swelling) or radiological signs of foot involvement at the time of the study. Our data suggest that involvement of the tendons and entheses may be more frequent in PsA patients than has thus far been supposed, even in cases of not particularly aggressive disease, and that clinical evaluation tends to underestimate these manifestations.Foot involvement is very frequent in patients affected by psoriatic arthritis (PsA). However, evaluation of the painful foot can be problematic, because it is often difficult to distinguish between arthritis, tenosynovitis, and enthesopathy. Plain radiographs can show bone erosion or other features of joint involvement, but give little information about the soft tissues. We therefore studied foot involvement in 31 PsA patients using high resolution sonography, and compared the results with the findings on x-ray and clinical examination. Ultrasound revealed pathological findings in a large proportion of the patients, most of whom exhibited no clinical (pain or swelling) or radiological signs of foot involvement at the time of the study. Our data suggest that involvement of the tendons and entheses may be more frequent in PsA patients than has thus far been supposed, even in cases of not particularly aggressive disease, and that clinical evaluation tends to underestimate these manifestations.

Viruses and cancers: possible role of hepatitis C virus

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 hepatocellular 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‐Hodgkins 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.

Mixed cryoglobulinaemia: a cross-road between autoimmune and lymphoproliferative disorders

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-Hodgkins 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, Sjùgrens 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.

Antibodies against hepatitis C virus in mixed cryoglobulinemia patients.

SummaryThe prevalence of antibodies against hepatitis C virus (anti-HCV) in an unselected series of 45 mixed cryoglobulinemia patients was assessed by an enzyme linked immunosorbent assay (Chiron ELISA HCV, Second Generation). The anti-HCV specificity was evaluated by a recombinant based immunoblot assay (Chiron RIBA HCV, Second Generation Assay). HBV-related markers and HIVAb were detected in the same samples. The prevalence of anti- HCV observed in mixed cryoglobulinemia was compared with 80 patients with other immunological systemic diseases. Anti-HCV were found in 91% of mixed cryoglobulinemia patients, and confirmed by RIBA in all cases; on the other hand, anti-HCV were practically absent in other control diseases. HBV markers were recorded in 49% of mixed cryoglobulinemia subjects; while HIVAb were constantly absent. These data give us new insights into the etiopathogenesis of mixed cryoglobulinemia.ZusammenfassungBei einer nicht selektierten Gruppe von 45 Patienten mit gemischter Kryoglobulinämie wurde mit ELISA (Chiron ELISA HCV, Second Generation) nach Anti-HCV-Antikörpern gesucht. Die Anti-HCV-Spezifität wurde mit einem auf rekombinantem Antigen basierenden Immunoblot-Assay (Chiron RIBA HCV, Second Generation) geprüft. Die Serumproben wurden außerdem auf Marker für HBV und auf Anti-HIV-Antikörper untersucht. Zum Vergleich wurden 80 Patienten mit anderen Erkrankungen des Immunsystems auf anti-HCV getestet. Antikörper gegen HCV fanden sich bei 91% der Patienten mit gemischter Kryoglobulinämie, sie wurden in allen Fällen mit RIBA bestätigt. In der Kontrollgruppe war der HCV-Test nahezu immer negativ. Bei 49% der Patienten mit Kryoglobulinämie fanden sich auch HBV-Marker, aber in keinem Fall Antikörper gegen HIV. Die Ätiopathogenese der gemischten Kryoglobulinämie erscheint durch diese Daten in einem neuen Licht.

Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis

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<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.

Fibromyalgia Features in Patients with Primary Sjögren's Syndrome: Evidence of a Relationship with Psychological Depression

The prevalence of musculoskeletal complaints suggestive of the fibromyalgia syndrome (FS) was evaluated in 30 patients with primary Sjögrens syndrome (1 degree SS) and in two control groups of patients with osteoarthritis (OA) and diabetes mellitus (DM). In addition, the presence of depressive state was investigated in patients and controls using the Hamilton rating scale and an Italian self-evaluating test. Fibromyalgia features were found in 14 1 degree SS patients (47%), in 21 OA (70%) and in 10 DM (33%) controls. 1 degree SS patients showed the highest prevalence (47%) of moderate-severe depression with respect to OA (20%) and DM (7%) groups (p less than 0.01). Furthermore, while FS features correlated closely with both tests for depression in 1 degree SS (p less than 0.001), this correspondence was absent or much less significant in the other disease groups. Finally, neither psychopathological features nor FS complaints appeared to be related to the other clinical and serological findings of 1 degree SS.