Rocco Misiani

Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus

BACKGROUND Essential mixed cryoglobulinemia is frequently associated with hepatitis C virus (HCV) infection. A beneficial effect of interferon alfa therapy has been reported, but we do not know whether the antiviral activity of the drug affects the clinical and biochemical manifestations of disease. METHODS In a prospective randomized, controlled trial, we studied 53 patients with HCV-associated type II cryoglobulinemia. A group of 27 patients received recombinant interferon alfa-2a thrice weekly at a dose of 1.5 million units for a week and then 3 million units thrice weekly for the following 23 weeks. The 26 control patients did not receive anything apart from previously prescribed treatments. All patients were then followed for an additional 24 to 48 weeks. RESULTS Interferon was usually well tolerated, but it was permanently discontinued in two patients because of atrial fibrillation and depression. Two of the 26 patients in the control group were lost to follow-up. After the treatment period, serum HCV RNA was undetectable in 15 of the remaining 25 patients who received interferon alfa-2a, but in none of the controls. In comparison with the control group, the 15 patients with undetectable levels of HCV RNA in serum had significant improvement in cutaneous vasculitis (P = 0.04) and significant decreases in serum levels of anti-HCV-antibody activity (P = 0.007), cryoglobulins (P = 0.002), IgM (P = 0.002), rheumatoid factor (P = 0.001), and creatinine (P = 0.006). After treatment with interferon alfa-2a was discontinued, viremia and cryoglobulinemia recurred in all 15 HCV RNA-negative patients. On resumption of treatment, three of four patients had a virologic, clinical, and biochemical response. CONCLUSIONS The therapeutic efficacy of interferon alfa-2a in HCV-associated cryoglobulinemia is closely related to its antiviral activity, thus supporting the idea that HCV infection may be a cause of this disease.

Hepatitis C virus infection in patients with essential mixed cryoglobulinemia

OBJECTIVE To study the association between hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia. SETTING Wards and clinics of the Ospedali Riuniti di Bergamo and Ospedale di Treviglio e Caravaggio, Italy. PATIENTS Fifty-one patients with essential mixed cryoglobulinemia associated with glomerulonephritis and 45 controls with noncryoglobulinemic glomerulopathies. MEASUREMENTS Antibodies to hepatitis C virus (anti-HCV) in sera from patients with essential mixed cryoglobulinemia and from controls, using two enzyme-linked immunosorbent assays (c100 ELISA and c22/c200 ELISA) and a recombinant immunoblot assay (4-RIBA); cryoprecipitate anti-HCV before and after use of dithiothreitol, a substance able to destroy IgM antibodies with rheumatoid factor activity, in patients with essential mixed cryoglobulinemia; serum HCV RNA by polymerase chain reaction in patients with essential mixed cryoglobulinemia. RESULTS In patients with essential mixed cryoglobulinemia, the c22/c200 ELISA detected anti-HCV in 98% of serum samples (95% CI, 90% to 100%), whereas the rate of reactivity remained at 2% (CI, 0% to 12%) in the control group (P less than 0.0001). These results were confirmed by the 4-RIBA in 66% of patients with essential mixed cryoglobulinemia. The study of cryoprecipitate by c100 ELISA showed anti-HCV in 41% (Cl, 28% to 56%) of patients. After dithiothreitol, the rate of reactivity increased to 94% (CI, 84% to 99%; P less than 0.0001 by the McNemar paired chi-square test), suggesting that the elimination of rheumatoid factor leads to unmasking of anti-HCV in cryoprecipitate. Polymerase chain reaction detected HCV RNA in 13 of 16 sera from patients with essential mixed cryoglobulinemia. CONCLUSIONS The extremely high prevalence of anti-HCV in serum and cryoprecipitate along with the frequently associated serum HCV RNA suggests a close relation between essential mixed cryoglobulinemia and chronic HCV infection.

HÆMOLYTIC-URÆMIC SYNDROME: DEFICIENCY OF PLASMA FACTOR(S) REGULATING PROSTACYCLIN ACTIVITY?

It is suggested that patients with the haemolytic-uraemic syndrome and related disorders (such as thrombotic thrombocytopenic purpura) lack a plasma factor which stimulates prostacyclin (P.G.I2) activity. Normal plasma would supply the missing factor and is a rational treatment for some life-threatening symptoms (thrombocytopenia, haemolytic anaemia, hypertension) of this syndrome.

Reduced umbilical and placental vascular prostacyclin in severe pre-eclampsia

Prostacyclin production was significantly depressed in foetal and placental vascular tissues from five patients with severe pre-eclampsia in comparison to vascular tissues from women with uncomplicated pregnancy. Such an abnormality may be responsible for a reduced blood flow and defective fetal nutrition thus playing a major role in the pathogenesis of this syndrome.

Prostacyclin and human foetal circulation.

Tissues from human umbilical cord arteries and placental veins generated much greater prostacyclin activity than vessels from normal adults. High prostacyclin generation could contribute to maintaining the low peripheral vascular resistance typical of foetal circulation in which blood pressure is low despite very high cardiac output.

Plasmapheresis in the treatment of acute renal failure in multiple myeloma

Three patients with multiple myeloma and severe acute renal failure were treated by repeated plasmapheresis. Recovery of renal function was observed in all. The pathogenetic role of light chains and the possible mechanisms responsible for renal damage are discussed. It is suggested that the removal of light chains by plasmapheresis may be of therapeutic value in this condition.

Management of Myeloma Kidney: An Anti-Light-Chain Approach

This report describes the course of 23 patients with multiple myeloma and severe renal failure treated with a combination of plasmapheresis, chemotherapy, and supportive measures. Eight of ten patients with acute renal failure (ARF) obtained recovery of renal function, and in five of them serum creatinine concentration returned to normal. The remaining two patients died before the effect of treatment could be evaluated. Eleven of 13 patients with chronic renal failure (CRF) had substantial, albeit incomplete, improvement in renal function. The extent of functional recovery appeared to depend on the type of renal lesions, probably related to the duration of exposure to light chains. The median survival of the whole series of patients was 9 months, and five patients lived longer than 3 years. No clear-cut difference in survival was found between the group with ARF and that with CRF, although the latter presented higher values of serum creatinine at the time of diagnosis and residual renal insufficiency after the completion of treatment. Moreover, no significantly different survival times were found when the group with complete recovery of renal function was compared to that with minor improvement. Thus, renal failure, with the availability of effective forms of treatment of uremia, did not play a major prognostic role in our series. In contrast, the response to chemotherapy appeared to be the outstanding factor conditioning the duration of survival in these patients.

Plasmatic regulation of vascular prostacyclin in pregnancy.

Activity of prostacyclin-stimulating factor was measured in six normal, non-pregnant women, six women in early normal pregnancy, six in late normal pregnancy, and six in late pregnancy complicated by severe pre-eclampsia. The activity was lower in the women in late pregnancy than in those in early pregnancy and the controls but was about normal in those with severe pre-eclampsia. These results may be relevant to the physiology of pregnancy and the pathogenesis of pre-eclampsia.

Familial deficiency of a plasma factor stimulating vascular prostacyclin activity.

Abstract We previously reported successful treatment with plasma in patients with thrombotic microangiopathy and defective vascular PGI2 activity and suggested that a defect in a plasma factor stimulating PGI2 synthesis might be implicated in the pathogenesis. We report here that in one of these patients the plasma defect was still detectable one year after clinical remission (without recurrence). Two of this patients four children had a similar, though less severe, plasma defect. The proposita is a 54-year-old woman with a clinical and laboratory picture of haemolytic uraemic syndrome. Unlike normal plasma, the patients plasma had a low capacity to stimulate PGI2 production by rat aortic rings (previously washed until their endogenous PGI2 activity was exhausted). After plasma treatment the patients plasma behaved normally in this respect, but again appeared deficient at out-patient follow-up. PGI2 stimulating activity was normal in two daughters but consistently low (20–50% of control) in both patients sons. None of them had any history or clinical signs of microangiopathic disorders. Detection of this plasma defect in apparently healthy subjects and in patients who have recovered from thrombotic microangiopathy episodes could have clinical implications.

Urinary albumin excretion in normal pregnancy and pregnancy-induced hypertension

We measured the urinary excretion of albumin in 67 healthy primigravidae, at monthly intervals, from 16 to 36 weeks of gestation and 12 weeks postpartum. Of the 67 primigravidae, 55 completed a normal pregnancy and 12 developed pregnancy-induced hypertension. In the latter group, an additional measurement of urinary albumin excretion was performed at 24 weeks postpartum. The aims of the study were: to look for changes of urinary albumin excretion during the progression of normal pregnancy; to assess if microalbuminuria could be an early feature of pregnancy-induced hypertension; to evaluate the effects of physical activity on the excretion of albumin in normal pregnancy and pregnancy-induced hypertension. In contrast with glomerular hyperfiltration and increased urinary total protein, two recognized characteristics of the pregnant state, we found that normal primigravidae, during the day, excrete significantly less albumin (p between less than 0.01 and less than 0.001) in comparison with the postpartum period and nonpregnant women. Normal primigravidae, as a group, showed parallel changes of urinary albumin excretion and diastolic blood pressure throughout pregnancy and postpartum, suggesting an important physiologic role of hemodynamic factors in regulating glomerular permeability to albumin. The daytime urinary albumin excretion in patients developing pregnancy-induced hypertension was significantly higher (p between less than 0.005 and less than 0.001) than in normal pregnancy from the 28th gestational week onwards. The increased urinary albumin excretion preceded the onset of hypertension and tended to persist long after blood pressure had returned to normal levels.(ABSTRACT TRUNCATED AT 250 WORDS)