Herpes simplex virus infection in pemphigus vulgaris: clinical and immunological considerations

ARTICLE

Auteur(s) : Giacomo Caldarola^1,2, Andrea Kneisel¹, Michael Hertl¹, Claudio Feliciani^1,2

¹Department of Dermatology and Allergology, Philipp Universität, Marburg, Germany
²Clinica Dermatologica, Università Cattolica del “Sacro Cuore”, 00168 Rome, Italy

accepté le 13 Février 2008

Pemphigus vulgaris (PV) is a rare life-threatening autoimmune disease, involving the skin and mucous epithelia, characterized by flaccid blisters and erosions. PV is associated with IgG antibodies directed against the keratinocyte cell-surface adhesion molecules, desmoglein 1 (DSG1) and 3 (DSG3) [1, 2]. These autoantibodies cause epidermal keratinocyte detachment (called acantholysis) of skin and mucous epithelia. In addition to the characteristic clinical phenotype, the diagnosis of PV is made by the histopathological findings, the detection of tissue-bound IgG with an intercellular staining pattern, the presence of serum autoantibodies by indirect immunofluorescence, and more recently, enzyme-linked immunosorbent assays (ELISA) with recombinant DSG3 and DSG1 [3]. This latter tool also provides a somewhat quantitative serological disease activity index. In fact, recently, Müller et al. showed a correlation between the IgG titers against distinct sudomains of DSG3 and the clinical activity of PV [4].

There is strong evidence for a genetic predisposition of PV, but familial cases are very rare [5]. Upon this predisposing genetic background, different environmental factors have been shown to be triggers implicated in the pathogenesis of pemphigus. The most evident association is with drug intake of thiol drugs, such as penicillamine and captopril. An association with other non-thiol drugs, such as rifampicin, cephalosporins and calcium channel blockers, has seen also reported [6]. Several other exogenous factors have been proposed as triggering or exacerbating PV, particularly diet (garlic and tannins), burns, X-rays, ultraviolet radiation, neoplasms, hormones [6] and stressful life events [7, 8].

The apparently transmissible nature of some pemphigus variants, such as endemic pemphigus foliaceus (or fogo selvagem), has suggested a possible role for viruses as triggering factors. Moreover, different cases of pemphigus have been reported to follow or to be associated with viral infections. Viruses, particularly of the herpetoviridae family, have been isolated from skin lesion of pemphigus patients [9, 10]. Despite the major progress made in establishing the diagnosis of pemphigus by more refined assays, such as the DSG3/DSG1 ELISA, the diagnosis of a secondary cutaneous virus infection in pemphigus still remains a clinical consideration.

We present here three PV patients with secondary herpes simplex virus 1 (HSV1) infection which largely mimicked a clinical relapse of underlying PV. Based on the clinical and immunological data of the three PV patients, we could not establish a relationship between the detection of HSV1 and the titers of DSG3-specific IgG autoantibodies. These findings stress the importance of considering secondary HSV infection in pemphigus patients showing unusual clinical presentation or resistance to immunosuppressive therapy.

Case reports

Case 1

Case 2

Case 3

Discussion

Thus, consideration of secondary HSV infection in pemphigus patients on chronic immunosuppressive treatment remains a clinical challenge and should be considered in cases of sudden flare-ups or with a refractory course not responsive to immunosuppressive treatment.

Since 1974, when Krain suggested a possible role of HSV in the pathogenesis of PV [12], several cases of PV induced or worsened by viral infections have been reported. Since a few cases of PV were reported upon vaccination with viral proteins [13, 14], viral infections were considered to be a possible triggering factor. Several reports have described pemphigus cases in association with HSV, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus and human herpesvirus-8 infection [15]. Particularly, the latter correlation has been largely studied by several authors, but controversial results have been obtained, presumably due to local factors [16, 17]. In 1999, Tufano et al. studied the prevalence of herpesvirus DNA in peripheral blood mononuclear cells (PBMCs) and skin lesions of PV patients by polymerase chain reaction. HSV1 and HSV2 DNA were detected in 50% of PBMCs and in 71% of skin biopsies of the PV patients [7]. HSV DNA in blood was always transient and was thus considered as a marker of acute infection [7], while HSV DNA in skin lesions was found to be present in virally induced or associated diseases, such as HSV-induced erythema multiforme [18]. Onset or exacerbation of PV has been found to be associated with HSV infection in several clinical studies, as reviewed by Ahmed et al. [19], Brenner et al. [12] and Ruocco et al. [20].

Different hypotheses have been suggested regarding the potential role of HSV in the pathogenesis of PV. Viral infection may induce upregulation of humoral and cellular pro-inflammatory factors, thus facilitating the outbreak of PV. HSV infection has been shown to induce high levels of interferon-γ and interleukins 4 and 10, in genetically predisposed subjects that may trigger or increase autoantibody production [21]. A second hypothesis suggests that viral infections induce the production of autoantibodies through “molecular mimicry”: an HSV-specific immune response induces tissue damage leading to the exposure of immunologically protected autoantigens (such as DSG1 or DSG3) which may then evoke a secondary autoimmune response which cross-reacts with the initial HSV-specific immune response [22] Finally, Kalra et al. recently suggested a role for HSV in perpetuating/slowing down the healing of PV lesions [23]. However, our data seem to suggest HSV infection as a concomitant event due to lack of normal epithelial defence in PV lesion, but without any pathogenic implication causing a PV worsening. In fact, our findings do not show an increase of antibody titers correlated with the clinical worsening (figure 2). Moreover, HSV infection could be facilitated by therapy induced immunosuppressive state of these patients, such as showed in other similar cases [24].

These case reports underline the importance of considering secondary HSV infections in PV patients on chronic immunosuppressive therapy. The HSV lesions mostly consisted of multiple, grouped, small (1-3 mm), round blisters arising from inflamed skin or mucosa. Although they clinically appeared to be somewhat different from the PV lesions, they are difficult to identify when they appear together with a flare-up of PV lesions [25].

We strongly recommended considering secondary HSV infections in those pemphigus patients who do not respond to a sufficient immunosuppressive regimen or show a sudden relapse after reaching partial or complete clinical remission. The prevalence of secondary HSV infection in chronic pemphigus is probably underestimated. These implications are particularly valid in light of the availability of potent antiviral drugs such as aciclovir.

Acknowledgements

References

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