Circulating plakin autoantibodies in a patient with erythema multiforme major: are they pathogenic or a manifestation of epitope spreading?

Erythema multiforme is a well-recognised entity but its pathogenesis remains elusive. Theories hypothesise a cell-mediated immune pathogenesis, however recent case reports have observed autoantibodies to the plakin family of proteins, suggesting a role for the humoral immune system. We present a case of erythema multiforme major with circulating desmoplakin autoantibodies in a 36-year old woman who was previously diagnosed with pemphigoid gestationis. The close correlation between the concentration of these autoantibodies and the severity of clinical disease strongly suggests a pathogenic role in her disease. As previous case reports have proposed, these autoantibodies may be directly pathogenic. Alternatively, the epiphenomenon of epitope spreading must be considered in the subset of patients with erythema multiforme major.

[Features of dynamics of sera cytokines in patients with erythema multiforme during immunotherapy].

AIM: Study the features of cytokine profile in patients with exudative erythema multiforme (EME) and dynamics of basal level of pro-inflammatory and anti-inflammatory cytokines during immunotherapy. MATERIALS AND METHODS: 39 adult patients with erythema multiforme were examined. The patients were split into groups based on therapy variant. One group (14 individuals) received Immunovac-VP-4 against the background of basic therapy; the other (12 individuals)--cagocel against the background of basic therapy; comparison group (13 individuals) received only basic therapy; 15 individuals composed a group of healthy individuals. All the patients had the level of pro-, anti-inflammatory and regulatory cytokines determined in blood sera by solid-phase EIA method by using Biosource (Austria) test-systems at the beginning of the study and after the therapy. RESULTS: In patients with exudative erythema multiforme Immunovac-VP-4 therapy facilitated a significant (p < 0.05) increase of serum IFN-gamma level, insignificant (p > 0.05) increase of IL-1beta and decrease of IL-17. Whereas cagocel lead to an increase of IL-4 (p > 0.05), IL-2, IFN-gamma (p < 0.05) and decrease of TGF-beta and IL-12 (p < 0.05). At the same time basic therapy facilitated a significant increase of IL-5 and decrease of IL-6, IL-12, IFN-gamma. CONCLUSION: Immunovac-VP-4 facilitates the increase of secretion of IFN-gamma, IL-1beta against the background of TGF-beta that facilitates normalization of cooperation of cells in immune response including against viral infections, and thereby influencing the trigger factor in EME patients.

From erythema multiforme to toxic epidermal necrolysis. Same spectrum or different diseases?

Erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute bullous disorders associated to different prognosis, mainly due to infections and drugs. More in particular EM in more than 90% is caused by infections (especially Herpes virus infection), while, on the other hand SJS and TEN are referable in more than 95% of cases to drugs. Distinction among these three forms is often controversal and still debated. An attempt to distinguish these forms has been possible mainly according to anamnesis, clinical presentation (morphology, involved sites, extension of lesions) and pathogenetic mechanisms, being on the contrary more difficult from an histopathological point of view. Nowadays a clear diagnosis and a distinction from other life-threatening diseases is possible with the integration of all the mentioned aspects. Moreover, this recognition should be as early as possible in order to perform a prognostic evaluation of the case and to start supportive cares and therapies as soon as possible.

[Effect of proteflazid on TLRs expression by mononuclear leukocytes of peripheral blood and epithelial cells of mucous membranes and skin in patients with herpes-associated erythema multiforme and erythema annulare centrifugum].

The article reports survey data on 23 patients with erythemas, including 19 patients with herpes-associated erythema multiforme (HAEM) and 4 patients with Darier's erythema annulare centrifugum (DEAC). Patients in the initial state (baseline) and after two weeks of therapy with proteflazid were characterized by measuring the levels of Toll-like receptor (TLR) expression in peripheral blood mononuclear cells (PBMC) and in epithelial cells of the throat and the skin. The TLR expression in PBMC and skin was assessed by flow cytometry with monoclonal antibodies (ICA) (Caltag Laboratories, USA; Hycult Biotech, Netherlands) against relevant antigens. In addition, patients were also characterized by the content of subpopulations of lymphocytes expressing surface markers CD3, CD4, CD8, CD16, CD21, CD23, CD72, CD25, and HLA-DR in the peripheral blood, which was measured by flow cytometry. The therapy with proteflazid in patients with both HAEM and DEAC led to normalization of the level of both T-cell and B-cell immunity, which was manifested by an increase in the total number of lymphocytes, CD3+, CD4+, CD21+, and CD72+. Measurements of the dynamics of TLR expression in the course of immunotherapy showed an increase in the number of TLR 2, 3, 4, 7, 8, and 9 in PBMC (which was especially pronounced for TLR2) and in epithelium of the pharyngeal mucosa and skin (increased expression of TLR3, 7, and 9).

Frequent detection of herpes simplex virus antigen in skin and peripheral blood CD34+ mononuclear cells from patients with graft-versus-host disease.

Viruses are implicated in the initiation or flare of graft-versus-host disease (GVHD) by virtue of their ability to activate antigen-presenting dendritic cells (DC). Herpes simplex virus (HSV) infects circulating CD34+ stem cell progenitors, favoring their differentiation into skin homing DC (CD1a+ Langerhans cells) that contribute to the development of an inflammatory skin rash known as HSV-associated erythema multiforme (HAEM). Following on these findings, we conducted a prospective study to examine whether HSV is also associated with GVHD. Skin biopsies and peripheral blood mononuclear cells (PBMC) were collected from 37 consecutive patients on admission before and after allogeneic hematopoietic stem cell transplantation (HSCT) and examined for HSV antigen (Pol) expression and the presence of Pol+CD34+ and Pol+CD1a+ cells. Sixteen patients developed a skin rash that was histopathologically consistent with GVHD (group I), 3 patients had a rash that was not GVHD (group II, EM-like) and 18 patients did not develop any rash after HSCT (group III). Skin biopsies from the group I patients were Pol negative pre-HSCT (baseline) but became Pol+ after the diagnosis of GVHD. The GVHD biopsies also contained Pol+CD34+ and Pol+CD1a+ cells, and these patients had a significant percentage of circulating Pol+CD34+ and Pol+CD1a+ PBMC. By contrast, the group II patients had Pol+ skin cells and Pol+CD34+ circulating PBMC at baseline that decreased post-HSCT. The group III patients had Pol negative skin and very few circulating Pol+CD34+ and Pol+CD1a+ PBMC at baseline that were not significantly changed post-HSCT. The data associate skin GVHD with HSV reactivation during conditioning and its propensity for nonreplicative infection of CD34+ PBMC that induces DC activation. Further studies are needed to better elucidate this association.

Peripheral blood eosinophil counts predict the prognosis of drug eruptions.

BACKGROUND: Previous studies indicated that eosinophils infiltrate the skin during drug eruptions and that counts may become elevated in circulation. However, little is known about the role of eosinophils in the prognosis of patients with drug eruption. OBJECTIVE: This study aims to investigate the correlation between circulating eosinophil counts and the prognosis of patients with drug eruption. METHODS: A total of 113 patients were enrolled in this study. Clinical features, peripheral blood eosinophil counts, and liver function were analyzed in patients and controls. RESULTS: Our study indicated that eosinophils changed dynamically in different types of drug eruption and that mean eosinophil counts in patients with erythema multiforme-type drug eruption were significantly higher than in patients with other types of eruption. Most patients with eosinophilia had poor liver function, prolonged corticosteroid use, and extended hospitalization, all of which indicate severe disease. CONCLUSIONS: Our data suggest that circulating eosinophil counts were positively correlated with the severity of the drug eruption. Therefore, corticosteroids may be needed to treat patients with eosinophilia in clinical practice.

Rowell's syndrome: presenting features of systemic lupus erythematosus.

A subset of patients with lupus erythematosus develops erythema multiforme-like skin lesions with speckled pattern of antinuclear antibodies, positive rheumatoid factor, anti-Ro (SS-A), and anti-La antibodies (SS-B), which known as Rowell's syndrome. We report an adolescent boy presented with erythema multiforme-like skin lesions and pericardial effusion; he fulfilled criteria of both Rowell's syndrome and systemic lupus erythematosus (SLE). Such initial presentation of SLE is rarely reported in literature.

Erythema multiforme in a newborn associated with acute acquired cytomegalovirus infection.

Erythema multiforme is exceptional in newborns, and none of the few available reports has revealed a clear etiologic agent, not even herpes simplex virus. Immunocompetent patients rarely present with cutaneous cytomegalovirus involvement, and few cases of cytomegalovirus-associated erythema multiforme have been described, none of them in newborns. We report the first case of erythema multiforme in a newborn associated with cytomegalovirus infection.

Characterising oral lesions in patients who presented with chronic vesiculobullous lesions during a 10-year period.

INTRODUCTION: Vesiculobullous lesions are a subset of lesons with an aetiologic spectrum that ranges from infection to aberrant mmune function. The bulk are chronic immune-mediated or autoimmune diseases in which inappropriate production of antibodies against auto-antigens results in the development of these conditions. METHODS: All departmenta patient records in the ten-year period were reviewed and those indicating a provisional diagnosis of oral chronic immune-mediated lesions were included in the study. Simple descriptive statistics were used. Chronic immune-mediated conditions included were lichen planus, pemphigus vulgaris, benign mucous membrane pemphigoid, including cicatricial pemphigoid, bullous pemphigoid, erythema multiforme and systemic lupus erythematosus. RESULTS: The files of forty-five patients (12 males, 33 females) who had been provisionally diagnosed with immune-mediated oral lesions during a ten-year period, from 2001 to 2010, were identified. Of these, 22 (49%) recorded final diagnoses of chronic immune-mediated conditions. CONCLUSION: This paper characterises the oral lesions of chronic immune-mediated conditions diagnosed in patients attending the oral medicine clinic during a ten-year period.

Transient natural killer deficiency in a boy with herpes simplex virus-associated recurrent erythema multiforme.

Erythema multiforme is characterized by itching macules, papules and bullae, symmetrically distributed on the dorsum of the hands. They can follow the administration of several drugs or infections with various agents, and in particular with herpes simplex virus. The recurrent variant is very rare, especially in the paediatric age group. We describe the case of a male adolescent with recurrent erythema multiforme caused by herpes virus and transient natural killer deficiency.

Anti-desmoplakin antibodies in erythema multiforme and Stevens-Johnson syndrome sera: pathogenic or epiphenomenon?

The pathophysiology of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) is unclear. Whether autoantibodies against desmoplakin (Dp) I and II play a pathogenic role or result from an epitope spreading phenomenon is uncertain. Our aim was to characterize the keratinocyte antigens recognized in EM, TEN and SJS. Of 33 patients studied, 2 had TEN, 1 SJS, 9 EM major and 21 EM minor, according to Roujeau's criteria. All sera were studied by indirect immunofluorescence (IIF), immunoblotting and immunoprecipitation. Twenty normal sera were used as controls. 10/33 sera reacted with polypeptides of 215 and/or 250-kDa molecular mass, which co-migrate with Dp I and II as assessed by an anti-Dp I and II monoclonal antibody on IB. In IP, none of the anti-Dp I and -Dp II 10 patient sera immunoprecipitated Dp I and/or II from radiolabeled keratinocyte extracts. Two of 10 patient sera (SJS, EM minor) reacted with DpI and II when denaturated by the IB procedure. The reactivity against intracellular antigens DpI and II as denaturated proteins may result from the epidermal damage produced by aggressive autoreactive T cells, playing therefore only a secondary role in the pathogenesis of the disease.

Two cases of pustular toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a life-threatening, immune-mediated reaction, characterized by severe cutaneous and mucosal blisters and erosions. It often presents with flu-like symptoms, followed by a maculopapular, urticarial, purpuric or erythema multiforme-like eruption, which then evolves into blisters and sheet-like erosions. Presentation with pustules, however, is not well described in the English literature, and may lead to delayed diagnosis. We present two unusual cases of TEN that initially presented with pustular lesions.

Toll-like receptor 9 polymorphism in patients with erythema multiforme, Stevens Johnson syndrome and Stevens Johnson syndrome/toxic epidermal necrolysis overlap syndrome.

BACKGROUND: "Toll like receptor" (TLR) 9 functions in stepping in of native immune system against different viral and bacterial pathogens and induction of adaptive immune response effectively. TLR 9 gene polymorphism makes host predisposed to microbial pathogens by affecting thefunctional capabilities of the receptor. OBJECTIVE: We aimed to determine if TLR 9 gene polymorphism makes a predisposition to "erythema multiforme" (EM), "Stevens Johnson syndrome" (SJS) and "Stevens Johnson syndrome/toxic epidermal necrolysis overlap syndrome" (SJS/TEN). METHODS: Forty-two patients clinically and/or histopathologically diagnosed as EM, SJS, and SJS/TEN overlap syndrome and 50 healthy control subjects were enrolled in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied for TLR 9 gene 1237 thymine/cytosine (T/C) polymorphism. Genotypes were determined according to bands occurring on agarose gel electrophoresis. RESULTS: In patients group, the frequencies of TT and TC genotypes were 73.8% and 26.2% while CC genotype wasn't detected. In control group, the frequencies of TT, TC and CC genotypes were 74%, 24%, and 2%. There wasn't a statistically significant difference for TT, TC and CC genotypes between patients and controls. The frequencies of T and C alleles were 84.5% and 15.5% in patients and 86% and 14% in controls, respectively. CONCLUSION: Our results showed that there isn't any association between TLR gene polymorphism and EM, SJS, SJS/TEN overlap syndrome (Tab. 1, Fig. 1, Ref. 30).

Autoantibodies to desmoplakin I and II in patients with erythema multiforme.

Erythema multiforme (EM) represents a syndrome of chronic recurrent inflammatory skin disease. Depending on the severity and extent of skin and mucosal involvement, it is defined either as EM minor or EM major. In this study we demonstrate the presence of autoantibodies (aAbs) against desmoplakin I and II, two major proteins of the desmosomal plaque, in six of six patients with the severe variant of EM, EM major. Light microscopic studies of lesional skin and mucous membranes localized in vivo bound immunoglobulin G (IgG) in a dotted desmosomal pattern along the cytoplasmic membranes of keratinocytes. By immunoelectronmicroscopy, in vivo bound IgG was confined to the desmosomal plaques. These findings were confirmed by indirect immunolocalization studies that demonstrated the presence of IgG aAbs in the serum of patients during active disease. These aAbs did not only bind to desmosomal plaques of epithelial cells where they colocalized with defined murine monoclonal antibodies directed against desmoplakin I and II, but also labeled the intercalated discs of myocardial cells. Biochemical characterization of circulating IgG aAbs revealed desmoplakin I and II as actual target autoantigens. By passive transfer of serum into newborn mice, in vivo binding of serum aAbs to keratinocytes was shown. The findings presented in this study imply a humoral immune response in certain patients with EM major and indicate a potential pathogenetic role of aAbs against desmoplakin I and II in this disease.

Rowell's syndrome: a rare but distinct entity in rheumatology.

Rowell's syndrome is a rare disorder characterised by an association of lupus erythematosus with erythema multiforme (EM)-like skin lesions. EM as the initial clinical presentation of systemic lupus erythematosus is also atypical and even rarer. We report the case of an 18-year-old girl admitted to our hospital with fever and polyarthralgia along with multiple discrete ill-defined target lesions with crust formation over forehead, cheek, external ears, scalp, upper chest and back (predominantly over sun-exposed areas) with ulceration over hard palate. Investigations revealed pancytopaenia, a positive rheumatoid factor, positive antinuclear antibody with a speckled pattern, anti-Smith antibody and strongly positive anti-Ro. Patient was diagnosed with Rowell's syndrome as per clinical and laboratory features. Majority of skin lesions including oral ulcerations subsided gradually after treatment with steroids and hydroxychloroquine.

Erythema multiforme-like contact reaction due to liquid-formulated 2,2-dibromo-3-nitrilopropionamide: involvement of cytotoxic T-lymphocyte reaction.

Erythema multiforme (EM)-like contact reactions are induced by exposure to various chemicals. We report two industrial workers from a paper mill who presented with generalized EM-like lesions 17 and 10 days, respectively, after accidental exposure to liquid-formulated 2,2-dibromo-3-nitrilopropionamide (DBNPA) 20%. The EM-like lesions appeared as subepidermal blisters associated with many necrotic or apoptotic keratinocytes and dense lymphocytic infiltration in the epidermis. Most of the infiltrating cells in the epidermis were CD8-positive T lymphocytes expressing cytotoxic molecules, including T cell-restricted intracellular antigen (TIA)-1, granzyme B and granulysin. Steroid pulse therapy failed to suppress the development of the lesions sufficiently, but cyclosporin 2.5-3 mg/kg successfully controlled the disease. DBNPA-induced, generalized EM-like eruptions may be mediated by cytotoxic T-lymphocytes.

A case of Good's syndrome complicated by erythema multiforme.

Good's syndrome (GS) is a rare, adult-onset combined B cell and T cell immunodeficiency with an associated thymoma. These patients have an increased risk of bacterial, fungal, viral and opportunistic infections. This report describes a 75-year-old female patient who presented with a full body rash and an anterior mediastinal mass. She underwent a biopsy of her rash and mass, which revealed erythema multiforme and WHO Type A thymoma, respectively. During her hospitalisation, she was also found to have oropharyngeal candidiasis, methicillin-susceptible Staphylococcus aureus bacteraemia and herpes simplex virus type 2 (HSV-2) skin lesions. Based on the number of infections and severity of her rash, an immunocompromised state was suspected. Immunological testing revealed a B cell and T cell deficiency as well as low serum immunoglobulins. This combination of hypogammaglobulinaemia and thymoma led to a diagnosis of GS. While there have been many case reports of GS, this is the first report of the immunodeficiency presenting with erythema multiforme.