Elsevier

Journal of Autoimmunity

Volume 65, December 2015, Pages 74-81
Journal of Autoimmunity

Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature

https://doi.org/10.1016/j.jaut.2015.08.008Get rights and content

Highlights

  • Data on patients with infectious in the absence of HCV infection are lacking.

  • Virus and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas.

  • Anti-infectious specific therapy is most frequently associated with sustained remission.

  • Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.

Abstract

In patients with infectious cryoglobulinemia vasculitis (CryoVas) in the absence of hepatitis C virus infection, data on presentation, therapeutic management and outcome are lacking. We conducted a nationwide survey that included patients with HCV-negative CryoVas. We describe here the presentation, therapeutic management and outcome of 18 patients with non-HCV infectious CryoVas and 27 additional patients identified form a systematic review of the literature. We included 18 patients, mean age 57.9 ± 13.5 years. Infectious causes were viral infections in 8 patients [hepatitis B virus (HBV) in 4, and cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each], pyogenic bacterial infection in 6 patients, parasitic infection in 2 patients, and leprosy and candidiasis in one case each. Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. Most cases received specific anti-infectious therapy as first-line therapy, sometimes associated with corticosteroids, achieving sustained remission in the majority of cases. Refractory or relapsing patients, frequently related to HBV infection, showed a complete remission after rituximab in addition to antiviral therapy. In contrast, corticosteroids and/or immunosuppressive agents used in the absence of anti-infectious agents were frequently associated with refractory CryoVas. Viral and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas. Antimicrobial therapy is commonly associated with sustained remission. Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.

Introduction

Cryoglobulinemia is defined as the presence of circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Cryoglobulinemia is sorted according to the classification by Brouet et al. [1]. Type I cryoglobulins are associated with lymphoproliferative disorders, while mixed cryoglobulins (MC) (type II and III) are associated with connective tissue diseases, lymphoproliferative disorders, and chronic infections. Since the discovery of hepatitis C virus (HCV) infection in 1989, it has become clear that HCV is associated with most cases of MC, found in 70%–90% of MC patients [2], [3], [4]. Cryoglobulinemia may be responsible for systemic vasculitis (CryoVas), with manifestations ranging from MC syndrome (purpura, arthralgia, and asthenia) to more serious lesions with skin, neurologic and renal involvement [5].

Recent studies have revisited the presentation, therapeutic management and outcome of CryoVas according to HCV screening and immunochemical typing. In HCV-related mixed CryoVas, optimal antiviral therapy is the standard of care for patients with mild to moderate disease activity, whereas rituximab may be used in addition to antiviral agents in patients presenting with severe or refractory disease [6], [7]. In non-infectious mixed CryoVas, rituximab plus corticosteroids showed in retrospective studies a greater therapeutic efficacy compared to corticosteroids or and alkylating agents plus corticosteroids to achieve complete clinical, renal and immunological responses. However, this regimen was associated with severe infections, particularly when high doses of corticosteroids were used [8]. In patients with type I monoclonal CryoVas, the use of alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib-based regimens represent interesting alternative options [9].

In patients with infectious mixed CryoVas in the absence of HCV infection, data on presentation, therapeutic management and outcome are lacking. In the present study, we describe features from patients with HCV-negative infectious mixed CryoVas included in the French CryoVas survey as well as additional patients identified from a systematic review of the literature.

Section snippets

Patients

The French CryoVas survey is a nationwide retrospective study that was initiated in February 2010 to describe the presentation and the efficacy and safety of treatments in patients with non-HCV CryoVas. Inclusion criteria for the study were as follows: 1) detectable cryoglobulinemia in the serum; 2) systemic vasculitis; and 3) diagnosis of CryoVas between January 1995 and July 2010. Exclusion criteria were the presence of anti-HCV antibodies. French hospital- and community-based units of

Characteristics of patients

Out of the 324 patients included in the CryoVas survey, 18 patients met the inclusion criteria and had HCV-negative infectious mixed CryoVas (Fig. 1) [8], [11]. Their characteristics are given in Table 1 and Table 2. The mean age at diagnosis was 57.9 ± 13.5 years, and 11 patients (61%) were female. Infectious causative agents were: viral infections in 8 patients [hepatitis B virus (HBV) in 4, cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each],

Discussion

We described in this study the presentation, therapeutic management and outcome of these patients through a personal series and the review of the literature, which represents the largest series of non-HCV infectious mixed CryoVas.

Our study provides for the first time the spectrum of infectious agents responsible for mixed CryoVas. Besides HCV infection, which is the most frequent cause of CryoVas, HBV infection, endocarditis, leishmaniasis and B. melitensis infection represent the main

Funding

None.

Authorship contribution

B.T., O.H., J-M.L., X.M., P.S., E.P. and P.C. designed the research; B.T., I.M., A.L., P.B., F.B., L.C., B.G., A.H., J-E.K., C.M., T.Q., L.S.-M., O.H., J-M.L., X.M., P.S., E.P. and P.C. collected data; and B.T. and P.C analyzed and interpreted data, and wrote the manuscript.

Conflict of interest disclosure

The authors declare no competing financial interests.

Acknowledgments

We wish to acknowledge the physicians who participated in the “CryoVas study group” (alphabetical order): Laurent Aaron, Sébastien Abad, Redouane Bakir, Pauline Belenotti, Lucas Benarous, Nathalie Beneton, Gilles Blaison, Claire Blanchard-Delaunay, Fabrice Bonnet, Frank Bridoux, Patrice Cacoub, Pascal Cathébras, Fabrice Carrat, Laurent Chiche, Olivier Chosidow, Bernard Combe, Christian Combe, Nathalie Costedoat-Chalumeau, Pierre Cougoul, Bernard Cribier, Gilles Defuentes, Elisabeth Diot,

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