Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie – GISC

Abstract

Background

Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined.

Aims

To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored.

Methods

In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45–70) were enrolled.

Results

The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1–14), rheumatoid factor was 200 U/L (range 20–5850), C4 was 12 mg/dl (range 2–31), ALT 71 U/L (range 36–114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis.

Conclusion

NUC therapy appeared to be safe and effective in CV-related HBV.

Introduction

Infection with hepatitis B (HBV) is a serious worldwide public health problem. It is estimated that about 350 million people are chronically infected with HBV. The clinical manifestations of HBV range from acute or fulminant hepatitis to various forms of chronic infection, including an inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma [1], [2].

About 20% of HBV patients develop extrahepatic manifestations; among them, polyarthritis nodosa and glomerulonephritis are the most severe. Other manifestations (e.g., dermatitis, poly-arthralgias and arthritis, respiratory disease, aplastic anemia) are rare and cryoglobulinemic vasculitis (CV) occurs in approximately 3% of patients [3], [4]. No association has been found between these manifestations and viral genotypes [3], [4]. Reported cases of HBV-related CV are rare, the most effective treatment is still unknown, as no definitive guidelines have been issued to date. The conventional immunosuppressive therapy used in rheumatologic disorders is not indicated in HBV-related CV, while antiviral therapy with nucleotide analogues seems to be the best treatment in these cases. Evidence on the efficacy of the antiviral treatment of HBV-related CV with nucleoside analogues is limited, since only case reports are presently available in the literature [5], [6], [7], [8], [9], [10], [11]. According to Brouet et al. [12], the cryoglobulinemias are classified in three types. In type I, the cryoglobulins are formed by monoclonal immunoglobulins only, commonly IgM. This type of cryoglobulins are associated with lymphoproliferative disorder (multiple myeloma or Waldenström's disease). In types II and III (so called mixed cryoglobulinemias, MC), the cryoglobulins are immune-complexes composed by polyclonal IgGs, the antigen(s), and monoclonal or policlonal IgMs, respectively. The IgM are endowed with rheumatoid factor activity, i.e., against polyclonal IgG [12], [13], [14]. Types II and III are associated with chronic viral infections (i.e., HBV and HCV), connective tissue diseases, and lymphoproliferative disorders.

The clinical manifestations of MC are due to the deposition of immune-complexes in several organs and tissues. MC may determine not only purpura, arthralgias and asthenia, but also more serious lesions of the skin (large ulcers), and neurologic and renal involvement [15], [16], [17], [18], [19]. The therapy of MC is based on immunosuppressive agents (steroids, cyclophosphamide, azathioprine, cyclosporine) for patients with mild-to-moderate disease, whereas more aggressive treatments, such as corticosteroids or plasmapheresis or high-dose cyclophosphamide, are needed in patients with severe disease [20], [21]. More recently, data on the efficacy and safety of anti-CD20 monoclonal antibodies in MC vasculitis have emerged [22], [23].

The purpose of this retrospective study was to assess the treatment in a group of patients with HBV-related CV.