The benefit of long-term interferon alfa therapy for symptomatic mixed cryoglobulinemia (cutaneous vasculitis/membranoproliferative glomerulonephritis) associated with chronic hepatitis C infection

The efficacy of long-term interferon therapy for chronic hepatitis C infection with symptomatic mixed cryoglobulinemia has not clearly been defined. We describe a patient with chronic hepatitis C, symptomatic mixed cryoglobulinemia (cutaneous vasculitis), and membranoproliferative glomerulonephritis (MPGN) who responded clinically, biochemically, and virologically to a 1-year course of interferon therapy. Interferon side effects were minimal. Relapse occurred when interferon was discontinued, and suppressive maintenance interferon therapy was required for clinical, biochemical, and virologic remission. During the 5th year of maintenance therapy, she developed potential side effects that necessitated discontinuation of interferon treatment. After treatment stoppage, a clinical, biochemical, and virologic remission was maintained for more than 1 year. However, the potential side effects, which included eye irritation, arthralgias, myalgias, fatigue, insomnia, memory loss, and depression, persisted. Ophthalmologic, rheumatologic, and neurologic evaluations were nondiagnostic. Psychometric testing revealed dementia and mood disorder. Because the disabling symptoms persisted after 9 months, a health-related quality of life assessment was carried out with the SF-36 survey. Compared with healthy individuals and patients with chronic hepatitis C, our case had a lower health-related quality of life assessment on six out of seven scales and on four out of seven scales of the SF-36 survey, respectively. This case report indicates that long-term maintenance interferon therapy was effective in the treatment of symptomatic mixed cryoglobulinemia and its renal complications and resulted in a clinical, biochemical, and virologic sustained response. It is postulated that the side effects of long-term interferon therapy in this setting may be problematic.     

Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis

PURPOSE OF REVIEW: Hepatitis C virus infection is the main cause of mixed cryoglobulinemia vasculitis. The disease expression of mixed cryoglobulinemia vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). Treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis may target either the viral trigger (hepatitis C virus) or the downstream B-cell arm of autoimmunity. This review focuses on recent advances in our understanding of the treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis. RECENT FINDINGS: Aggressive antiviral therapy with Peg-IFNalpha and ribavirin should be considered as induction therapy for hepatitis C virus-mixed cryoglobulinemia vasculitis with mild to moderate disease severity and activity. In patients presenting with severe disease, an induction phase of immunosuppression is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab and Peg-IFNalpha plus ribavirin appears logical as it may target both the viral trigger (hepatitis C virus) and cryoglobulin-producing B-cells. SUMMARY: Antiviral therapy and rituximab are the main therapeutic options in hepatitis C virus-mixed cryoglobulinemia vasculitis. Further studies are needed to better define the therapeutic strategy.     

Hepatitis C virus infection with and without cryoglobulinemia as a case of Churg-Strauss syndrome

Chronic hepatitis C virus (HCV) infection may be associated with numerous immune disorders, with vasculitis including polyarteritis nodosa, or with both. Cryoglobulinemia, which is often present, can also be expressed by vasculitis. We describe 2 cases of Churg-Strauss syndrome (CSS) in patients with HCV infection. We found no previous case of CSS accompanying HCV infection in the literature. The current patients were women aged 40 and 66 years. In both cases, a clinical and laboratory pattern suggesting CSS was found before the HCV infection was discovered. One patient had cryoglobulinemia. One patient was successfully treated with interferon (IFN). The other was treated for 18 months with IFN and corticosteroids. Second-line therapy consisting of IFN with ribavirin was successful. The emergence of HCV infection may have led to an induced form of CSS. The relationship among HCV, cryoglobulinemia, and CSS is not clear, but may be similar to that existing between polyarteritis nodosa and hepatitis B virus. These observations suggest that IFN-alpha therapy may be effective against CSS in HCV infected patients with or without cryoglobulinemia.     

Relapsing polychondritis, chronic hepatitis C virus infection, and mixed cryoglobulemia

OBJECTIVE: Review of relapsing polychondritis (RP) and its association to chronic hepatitis C virus (HCV) infection and mixed cryoglobulinemia. METHODS: A case of RP associated with HCV infection is reported. The English language medical and scientific literature was reviewed for RP, hepatitis C, and its relation to other connective tissue diseases from February 1966 to January 2003 using MEDLINE. RESULTS: RP is an uncommon, multisystem disease of unknown etiology characterized by recurrent inflammation of cartilaginous and related tissues, being associated with other diseases in 30% to 35% of cases. HCV infection is a systemic illness with a propensity to trigger or exacerbate autoimmune disorders: eg, essential mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and leukocytoclastic and systemic vasculitis. We could find no previous report of an association between RP with HCV and mixed cryoglobulinemia. Treatment with interferon gamma and ribavirin (IR) not only induced an undetectable viral load, but also resolved symptoms of RP. CONCLUSIONS: We report a patient with RP, HCV, and mixed cryoglobulinemia. It is unknown if there is a cause-effect or chance relationship. Treatment with IR improved the symptoms of RP. It is not known whether the effects of IR were directly on the RP or suppressed RP indirectly through the actions on the viral load or active hepatitis.     

Kidney disease in patients with chronic hepatitis c

There is an increasing recognition of the association between chronic hepatitis C virus infection and glomerular diseases. Renal complications may be the presenting manifestation of hepatitis C virus infection. Patients may present with signs and symptoms of cryoglobulinemic systemic vasculitis, proteinuria, microscopic hematuria, acute renal failure, or nephrotic syndrome. The pathogenesis of hepatitis C virus associated with renal disease remains incompletely understood; however, deposition of circulating immune complexes in the subendothelial space and mesangium in the glomeruli seems to play a major role. The most common renal pathology associated with hepatitis C virus infection is type I membranoproliferative glomerulonephritis with or without cryoglobulinemia. In patents who do not have significant renal impairment, combination therapy with interferon alfa (IFN-α) and ribavirin seems to be the treatment of choice, although the experience with this combination is quite limited in patients with renal involvement. A prolonged course of high-dose IFN-α has been most commonly used for these patients with significant success, but relapse of hepatitis C viremia and renal disease after discontinuation of therapy have frequently occurred.     

Renal manifestations associated with hepatitis C virus

Among the several types of chronic glomerulonephritis (GN) described in association with hepatitis C virus (HCV) infection, cryoglobulinemic glomerulonephritis is by far the most frequent. It is usually associated with type II cryoglobulinemia with IgM k rheumatoid factor. It is a membranoproliferative GN, which shows some distinctive histologic features (intraglomerular monocyte infiltration, intraluminal thrombi due to massive precipitation of cryoglobulins, renal vasculitis), has a chronic course with acute recurrent episodes that can be controlled by corticosteroids more than by antiviral therapy (interferon alpha). More controversial is the association with type I non-cryoglobulinemic membranoproliferative GN, which has been found in some series from the USA and Japan but not in others. The demonstration of HCV antibodies and/or HCV-RNA in other types of chronic glomerulonephritis is usually reported in a small minority of cases suggesting the possibility of a coincidental finding more than an etiologic factor.     

Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations

Hepatitis C viral infection is currently the leading cause of chronic hepatitis and cirrhosis. It also is a major predisposing factor for the development of hepatocellular carcinoma. It is estimated that approximately 1-2% of patients with hepatitis C infection have nonhepatic manifestations that are protean in nature. In this report, we describe six unusual cases of nonhepatic manifestations: abdominal vasculitis in two, peripheral neuropathy in two, and one patient each with central nervous system vasculitis and necrotizing cutaneous vasculitis. All patients had cutaneous vasculitis and cryoglobulinemia. None of our patients had cirrhosis, yet three of the six patients died. Because of the severe manifestations, aggressive therapy was instituted with interferon, immunosuppressive medications, i.v. immunoglobulin, and plasmapheresis. Our report underscores the importance of recognizing nonhepatic manifestations in patients with hepatitis C infection that may be associated with high morbidity and mortality.     

Recovery from hepatitis C virus-positive cryoglobulinaemic glomerulonephritis after interferon therapy

The association between mixed cryoglobulinaemia and chronic hepatitis C virus infection has recently been described. Cryoglobulinaemic glomerulonephritis, a complication of mixed cryoglobulinaemia, is usually treated with immunosuppressive therapy, but, given the presence of viral infection, this therapy is no longer recommended. This report concerns a case of a 30-year-old patient with cryoglobulinaemic glomerulonephritis, refractory to steroid treatment, in whom recovery from hepatitis C virus infection was obtained as well as from cryoglobulinaemic glomerulonephritis after interferon therapy. The clinical symptoms and laboratory tests were normal after prolonged interferon therapy and, 3 years after the end of treatment, the patient is free from disease.     

HCV and extrahepatic diseases

Besides being a hepatotropic virus and a common cause of chronic hepatitis, hepatitis C virus (HCV) has been linked to a variety of extrahepatic immunological manifestations. The high prevalence of HCV infections in some of these conditions suggests an important pathogenetic role of the virus. The recent observation that HCV infects peripheral blood mononuclear cells, such as CD8+ T lymphocytes, CD19+ B lymphocytes and monocytes/microphages, has given an insight into the possible mechanisms of HCV associated autoimmunity. In the clinical practice it is recommended not only to search for symptoms and signs of autoimmune disorders in patients with chronic hepatitis C, but also to test for hepatitis C virus infection patients with extrahepatic conditions known to be related to HCV. Even if the occurrence of autoimmune disorders or the exacerbations of autoimmune diseases has been reported during interferon therapy, antiviral therapy is effective in treating some of the extrahepatic disorders associated with HCV, namely mixed cryoglobulinemia and membranoproliferative glomerulonephritis. The extrahepatic manifestations associated with hepatitis C virus infection are reviewed according to the available data and the option of interferon therapy is discussed.     

Plasmapheresis in cryoglobulinemic neuropathy: a clinical study

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. Plasmapheresis appears to be a useful adjunct to conventional therapy in the treatment of anti-GBM nephritis, severe dialysis-dependent forms of pauciimmune RPGN, cryoglobulinemia, and HUS-TTR Therapy with plasmapheresis produced a marked decrease in cryoglobulin levels and a subsequent relevant clinical improvement of cutaneous lesions and renal function. In cryoglobulinemia, plasmapheresis can be used as effective further therapy to minimize cutaneous, renal and/or neurologic involvement.     

Treatment of hepatitis C cryoglobulinemia: Mission and challenges

Opinion statement Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-a and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.     

Polyarteritis nodosa and cryoglobulinemic glomerulonephritis related to chronic hepatitis C

CASE REPORT: A 53-year-old man with hepatitis C virus (HCV) infection underwent cholecystectomy for presumed cholecystitis. Gallstones were not present, and histological examination demonstrated medium-sized arteritis, consistent with polyarteritis nodosa (PAN). The patient later developed rapidly progressive glomerulonephritis. Kidney biopsy demonstrated cryoglobulinemic glomerulonephritis. Because of the severity of the patient's vasculitic manifestations, treatment included pulse methylprednisolone followed by oral prednisone and monthly intravenous cyclophosphamide for 6 months. During treatment, microhematuria resolved, proteinuria decreased, and serum creatinine concentration stabilized. The patient subsequently underwent treatment for HCV with interferon resulting in a marked decrease in HCV RNA. The patient has had no relapse of his vasculitis, his renal function is stable, and viral load remains low after completing 36 weeks of interferon. CONCLUSION: Life-threatening vasculitis related to HCV was successfully treated with immunosuppressive therapy. After obtaining clinical remission, antiviral therapy was instituted, resulting in a dramatic decrease in HCV RNA.     

HCV infection and extrahepatic manifestations

Hepatitis C virus infection is associated with various extrahepatic manifestations such as mixed cryoglobulinemia, membranoproliferative glomerulonephritis and porphyria cutanea tarda. The link between mixed cryoglobulinemia and hepatitis C virus infection is actually well known. Interferon alpha therapy decreases hepatitis C viremia and improves the clinical signs and biochemical abnormalities of cryoglobulinemia. The rare combination of hepatitis C and panarteritis nodosa has still not been confirmed. The sicca syndrome also seems to be associated with hepatitis C virus, but this is not the typical Sjogren's syndrome. It is not yet well established if hepatitis C virus plays a pathogenic role in the development of thyroid dysfunction and autoimmune thyroiditis. Probably interferon therapy may be implicated in the development in this and other extrahepatic manifestations of hepatitis C virus infection. Although an epidemiological association of hepatitis C with lichen planus, neuropathies and other diseases has been observed, the etiological role and the pathogenic involvement of the hepatitis C infection remains unclear. Extrahepatic clinical manifestations are frequently observed in hepatitis C virus patients and involve primarily the joints, muscles, and skin. The most frequent immunological abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti-smooth muscle antibodies.     

Treatment with pegylated interferon and ribavirin for hepatitis C virus-associated severe cryoglobulinemia in a liver/kidney transplant recipient

End-stage liver disease after hepatitis C virus (HCV) infection is the most common indication for liver transplantation, accounting for over 40% of liver transplants performed. Combined liver/kidney transplantation is being performed more frequently, in part because HCV infection may coexist with conditions that damage the kidney, such as diabetes and cryoglobulinemia. Unfortunately, HCV hepatitis and cryoglobulinemia may recur after liver transplantation and adversely affect graft and patient survival. In immunocompetent patients, interferon (IFN) and ribavirin (RBV) combination therapy is often able to control cryoglobulinemic syndrome. Very little data are available on liver transplant recipients, whereas IFN usually is not indicated in kidney transplant recipients because of early reports of steroid-induced rejection after its administration. Successful treatment of cryoglobulinemia with IFN/RBV in recipients of combined liver/kidney transplant has not been previously reported. We treated 1 recipient of a combined liver and kidney transplant with pegylated-IFN/RBV combination therapy. The patient developed HCV recurrence associated with cryoglobulinemia and severe cutaneous peripheral and neurologic manifestations. Treatment with pegylated-IFN-alpha2b and RBV for 12 months cured the cryoglobulinemic vasculitis and allowed the sustained eradication of HCV with no significant changes in kidney function.     

Membranoproliferative glomerulonephritis and leukocytoclastic vasculitis without cryoglobulin in chronic hepatitis C virus infection

The etiopathogenesis of extrahepatic manifestations including vasculitis in the context of HCV infection is still unknown. We report a case with lethal extrahepatic manifestations due to chronic hepatitis C virus (HCV) infection. The patient presented leukocytoclastic vasculitis, sensorimotor neuropathy and membranoproliferative glomerulonephritis with positive rheumatoid factor but lacked cryoglobulin. Hypocomplementaemia and deposition of IgM and C3 in the vascular lesion and glomeruli suggested that immune complex disease played a role in the pathogenesis of extrahepatic manifestations independent of cryoglobulin. Although HCV was successfully eliminated by treatment with interferon alpha, she died of cryptococcal infection.     

Management of Hepatitis C Virus-related Mixed Cryoglobulinemia

Mixed cryoglobulinemia is a chronic immune complex-mediated disease strongly associated with hepatitis C virus (HCV) infection. Mixed cryoglobulinemia is a vasculitis of small and medium-sized arteries and veins, due to the deposition of complexes of antigen, cryoglobulin and complement in the vessel walls. The main clinical features of mixed cryoglobulinemia vasculitis include the triad of palpable purpura, arthralgias, and weakness, and other pathological conditions such as glomerulonephritis, peripheral neuropathy, skin ulcers, and widespread vasculitis. The treatment of HCV-related mixed cryoglobulinemia is difficult due to the multifactorial origin and clinical polymorphism of the syndrome. It can be directed to eradicate the HCV infection, suppress the B-cell clonal expansion and cryoglobulin production, or ameliorate symptoms. The choice of the most appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement.     

Effects of Combined Antiviral Therapy on Asymptomatic Mixed Cryoglobulinemia in Naive Patients with Chronic Hepatitis C Virus Infection: A Preliminary Study

The clinical spectrum of mixed cryoglobulinemia embraces several manifestations: recurrent vascular purpura, weakness, arthralgia/arthritis, glomerulonephritis, peripheral neuropathies, and Raynaud's phenomenon. Mixed cryoglobulinemia is currently treated with steroids, low–antigen content diet, immunosuppressors, plasma exchange, and antiviral therapy, namely, α -interferon alone or, more recently, in association with ribavirin. In the present research, we verified the effectiveness of combined therapy with interferon and ribavirin on asymptomatic mixed cryoglobulinemia in naïve (never treated before) patients with chronic hepatitis C. We enrolled 50 consecutive patients, 31 males and 19 females, with chronic hepatitis C who showed a sustained response to combined antiviral therapy (interferon and ribavirin). Before treatment, cryoglobulins were detected in 25 subjects (50%). Only 1 of the 25 patients with asymptomatic mixed cryoglobulinemia had persistence of cryoglobulins at the end of the follow-up period. Unexpectedly, in 7 of 25 subjects without mixed cryoglobulinemia before treatment, cryoglobulins became detectable after antiviral therapy. Our present study first reports the onset of asymptomatic mixed cryoglobulinemia in hepatitis C virus patients after clearance of the virus from blood obtained with a combined antiviral treatment. Possible explanations are discussed. Our data also suggest that the appearance of a clinically evident mixed cryoglobulinemia cannot be excluded in this kind of subject.     

Hepatitis C virus-related cryoglobulinemia and glomerulonephritis: pathogenesis and therapeutic strategies

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. MC is a non-neoplastic B cell lymphoproliferative process induced by HCV in an antigen-driven mechanism. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. Glomerulonephritis is predominantly associated with MC, and almost always takes the form of membranoproliferative glomerulonephritis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. The treatment of these virus-related diseases must be individualized on the basis of the severity of clinical symptoms. Antiviral therapy with interferon alpha and ribavirin (the currently recommended treatment of HCV infection) may be successful in patients with mild-to-moderate disease, but sustained responses are uncommon. In case of severe and rapidly progressive disease, although it is capable of suppressing viremia and cryoglobulinemia, antiviral therapy is not fully effective in controlling the inflammatory and self-perpetuating reaction consequent to the deposition of cryoglobulins in the glomeruli and vessel walls. In such cases, a short course of steroids and cytotoxic drugs (with or without plasmapheresis) may be needed to improve the vascular manifestations and decrease the production of cryoglobulins. Once the acute disease flare has been controlled, antiviral therapy may be administered to eradicate HCV, the causative agent of the cryoglobulinemic syndrome. In patients in whom antiviral therapy is ineffective, contraindicated or not tolerated, rituximab, a monoclonal anti-CD20 antibody, may be an alternative to standard immunosuppression.     

Perforations digestives itératives secondaires à une cryoglobulinémie essentielle et au cytomégalovirus : à propos d’un cas

Cryoglobulinemia associated vasculitis is usually related to hepatitis C virus. Clinical features include purpura, glomerulonephritis, or peripheral neuropathy. Intestinal involvement in cryoglobulinemia is rare and has a poor prognosis. It often leads to a therapeutic with immunosupressive drugs. The related immunodepression exposes to a reactivation of cytomegalovirus (CMV) infection that may also be potentially responsible for intestinal injury. We report a 68-year-old man who presented with iterative intestinal perforations secondary to a cryoglobulinemia vasculitis and then to a CMV infection.