SEARCH

SEARCH BY CITATION

Keywords:

  • autoimmunity;
  • B-cell clone;
  • hepatitis C;
  • lupus erythematosus;
  • rituximab

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References

Abstract.  Böckle BC, Baltaci M, Ratzinger G, Graziadei I, Vogel W, Sepp NT (Innsbruck Medical University, Anichstrasse, Innsbruck, Austria). Hepatitis C and autoimmunity: a therapeutic challenge (Case Report). J Intern Med 2012; 271: 104–106.

Hepatitis C virus (HCV) infection causes not only acute and chronic liver disease, but also extrahepatic symptoms. To our knowledge, this is the first case report of a patient who developed simultaneously subacute cutaneous lupus erythematosus and a small CD20+ B-cell clone because of chronic HCV infection and relapse after standard of care therapy (pegylated interferon plus ribavirin). Treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, was successful.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References

In addition to acute and chronic liver disease, hepatitis C virus (HCV) infection causes extrahepatic manifestations (EHMs). About 60% of HCV-positive patients develop at least one EHM during the course of the disease; in particular, autoimmune disorders and lymphoma [1–3].

The pathogenetic link between HCV and the immune system in inducing both autoimmunity and lymphoproliferation is still not fully understood [4]. Clinical studies have focused mainly on the diagnostic characteristics of the EHMs of HCV infection, whereas few have addressed the therapeutic management [5].

Case

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References

In 2004, a 49-year-old Caucasian man with chronic HCV (genotype 3a) infection was treated with pegylated interferon alpha-2a (INF-α 2a 180 μg 1× per week) and ribavirin (800 mg day−1) for 6 months until March 2005. The patient responded only partially. No further therapy was administered.

In August 2009, he suddenly developed erythematous-to-violaceous scaling with well-demarcated annular plaques on the trunk, neck and arms (Fig. 1). The diagnosis of subacute cutaneous lupus erythematosus (SCLE) was made on the basis of laboratory values (positive Ro/SS-A antibodies and elevated immune activation parameters including ß2microglobulin, neopterin and interleukin-2 receptor) and a skin biopsy (Fig. 1).

image

Figure 1.  Clinical findings (a, b): (a) Clinical presentation of hepatitis C virus-induced subacute cutaneous lupus erythematosus; the patient initially presented with erythematous-to-violaceous scaling with well-demarcated annular plaques on the trunk, neck and arms. (b) The skin lesions resolved 5 months after initiation of rituximab treatment. Histopathological findings (c, d): Skin biopsy specimens from the back; (c) showing a dense perivascular and periadnexal lymphocytic infiltrate, most notably in the upper dermis. Dermal mucin depositions were observed between collagen bundles. (d) Characteristically, interface dermatitis with vacuolar changes and basement membrane zone thickening were observed. Haematoxylin–eosin staining; magnification: (c) ×40, (d) ×100.

Download figure to PowerPoint

Furthermore, the patient had evidence of lymphoproliferation. A small B-cell clone consisting of CD20+ CD5-CD79+ FMC7+ Kappa+ circulating lymphocytes was identified by flow cytometry. The results of bone marrow biopsy and abdominal and lymph node ultrasound were normal.

He initially showed a good response to treatment with methylprednisolone (1 mg kg−1 body weight) and hydroxychloroquine (6 mg kg−1 body weight). During tapering of the corticosteroid dose, recurrent flare-ups of SCLE were observed, and therefore, reduction of the corticosteroid dose to less than 0.3 mg kg−1 body weight was not possible. Furthermore, the patient developed a pronounced relapse of the SCLE after 4 months. An alternative therapeutic approach was required, and subsequently six infusions of rituximab (375 mg m−2 body surface area, every second week) were administered. HCV RNA levels did not further increase and the circulating B-cell clone was no longer observed. Moreover, several laboratory values that had been previously elevated (i.e. liver enzymes, immune activation parameters, rheumatoid factor and particularly Ro/SS-A antibodies) normalized during rituximab treatment. Subsequently, pegylated INF-α 2b (120 μg 1× per week) in combination with ribavirin (1000 mg day−1) was administered for 12 months and achieved a sustained virological response (undetectable HCV RNA). Complete resolution of the skin lesions has been observed to date.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References

In addition to HCV, other viruses may be potential aetiological or triggering agents in the pathogenesis of systemic lupus erythematosus (SLE). Chronic HCV infection can induce clinical and serological features that may co-occur and therefore mimic SLE. Interestingly, our patient developed SCLE and Ro/SS-A antibodies – two features that have been described only rarely in conjunction with chronic HCV infection [6].

Further, there have been several reports of SLE that developed during INF-α treatment of chronic HCV infection [7]. The long timeframe between INF-α therapy and the occurrence of SCLE in our patient makes the possibility of INF-α-induced SCLE unlikely.

In our patient, SCLE was unexpectedly refractory to conventional treatments suggesting that HCV was the trigger for SCLE. To find a therapeutic regimen for this patient in this situation was challenging; INF-α may provoke a flare-up of SCLE, but long-term therapy with high doses of corticosteroids are not compatible with active replicating HCV infection.

Chronic HCV infection is associated with the expansion of B-cell clones that may lead to autoimmunity [8]. The phenotypic characterization of these B-cell clones (e.g. CD20+ CD5+, CD5-CD20+ and CD5+ BAFF+) has been reported [9]. Our patient had a small circulating CD20+ CD5-CD79+ FMC7+ Kappa+ B-cell clone. Thus, a staged therapeutic strategy was chosen. An induction phase of immunosuppression with rituximab was necessary in order to inhibit HCV-induced B-cell activity. It is interesting that previous phase III trials of rituximab for the treatment of SLE have failed to demonstrate superiority of this agent over placebo plus conventional therapy. By contrast, in our patient, this targeted therapy depleted his particular CD20+ B-cell clone. Consequently, the SCLE resolved and Ro/SS-A antibodies were no longer detectable. This is remarkable because, according to previous results, rituximab treatment does not affect the generation of antibodies against RNA-binding proteins (Smith/RNP, Ro and La), which are thought to be produced by long-lived CD20- plasma cells. Hence, it is tempting to speculate that in this case, the HCV-induced specific CD20+ B-cell clone triggered the SCLE and also Ro/SS-A positivity. The response to rituximab treatment emphasizes the aetiological role of CD20+ B-cell clones in provoking SCLE in chronic HCV infection. Therefore, this may also have an impact on the therapeutic administration of rituximab in SLE in general.

Subsequently, in order to eliminate the causal disease, the slow response to antiviral treatments (INF- α and ribavirin) has to be awaited. In summary, we suggest that the discovery and phenotypic characterization of B-cell clones will be the key to successful therapy in patients with SLE as well as HCV-induced autoimmune disorders.

Conflict of interest statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References

No conflict of interest was declared.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case
  5. Discussion
  6. Conflict of interest statement
  7. References
  • 1
    Böckle BC, Sepp N. Hepatitis C virus and autoimmunity. Autoimmun Highlights 2010; 1: 2335.
  • 2
    Marcos M, Alvarez F, Brito-Zeron P et al. Chronic hepatitis B virus infection in Sjogren’s syndrome. Prevalence and clinical significance in 603 patients. Autoimmun Rev 2009; 8: 61620.
  • 3
    Sousa GM, Oliveira RC, Pereira MM, Parana R, Sousa-Atta ML, Atta AM. Autoimmunity in hepatitis C virus carriers: involvement of ferritin and prolactin. Autoimmun Rev 2011; 10: 2103.
  • 4
    Sansonno L, Tucci FA, Sansonno S, Lauletta G, Troiani L, Sansonno D. B cells and HCV: an infection model of autoimmunity. Autoimmun Rev 2009; 9: 934.
  • 5
    Cacoub P, Delluc A, Saadoun D, Landau DA, Sene D. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis 2008; 67: 2837.
  • 6
    Ramos-Casals M, Munoz S, Medina F et al. Systemic autoimmune diseases in patients with hepatitis C virus infection: characterization of 1020 cases (The HISPAMEC Registry). J Rheumatol 2009; 36: 14428.
  • 7
    Niewold TB, Swedler WI. Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C. Clin Rheumatol 2005; 24: 17881.
  • 8
    Zuckerman E, Slobodin G, Kessel A et al. Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection. Clin Exp Immunol 2002; 128: 3538.
  • 9
    Toubi E, Gordon S, Kessel A et al. Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J Autoimmun 2006; 27: 1349.