Iakov Shimanovich

Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases.

Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal‐epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long‐term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo‐plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders.Treatment with rituximab leads to depletion of pathogenic B‐cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies.Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m2 i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment.The present consensus statement of German‐speaking derma‐tologists,rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins.

Background  Pemphigus is a life‐threatening autoimmune blistering disease usually treated with high‐dose corticosteroids and other immunosuppressants. However, this regimen may prove inadequate in severe cases and cause dangerous side‐effects. While protein A immunoadsorption (PAIA) induces a rapid remission in severe pemphigus, the disease usually recurs once the treatment is stopped. In contrast, anti‐CD20 antibody rituximab has a delayed onset of action but may lead to a long‐term remission of pemphigus.

Anti‐p200 pemphigoid: A novel autoimmune subepidermal blistering disease

Anti‐p200 pemphigoid is a recently defined autoimmune subepidermal blistering disease characterized by circulating and tissue‐bound autoantibodies to a 200‐kDa protein (p200) of the dermal–epidermal junction (DEJ). This DEJ constituent is thought to be important for adhesion of basal keratinocytes to the underlying dermis. While the exact identity of p200 remains unknown, it has been demonstrated to be immunologically and biochemically distinct from all major autoantigens of the DEJ, including bullous pemphigoid antigens 180 and 230, laminin 1, 5 and 6, α6β4 integrin, and type VII collagen. Clinically, most reported cases present with tense blisters as well as urticarial papules and plaques, closely resembling bullous pemphigoid. Histopathological examination of lesional skin biopsies shows subepidermal split formation and superficial inflammatory infiltrate typically dominated by neutrophils. Immunopathologically, linear deposits of immunoglobulin (Ig)G and C3 are detected along the DEJ by direct immunofluorescence microscopy of perilesional skin. Indirect immunofluorescence microscopy of patients’ sera on NaCl‐split human skin demonstrates circulating IgG autoantibodies labeling the dermal side of the split. By immunoblotting, these autoantibodies recognize a 200‐kDa protein of human dermis. Biochemical characterization of the p200 molecule revealed a noncollagenous N‐glycosylated acidic protein with an isoelectric point of approximately 5.5. We present an overview of the pathogenesis, clinical features, diagnosis and treatment of this new disease entity.

Autoantibodies against epidermal transglutaminase are a sensitive diagnostic marker in patients with dermatitis herpetiformis on a normal or gluten-free diet

BACKGROUND Dermatitis herpetiformis (DH) is a cutaneous manifestation of gluten-sensitive enteropathy (celiac disease). Patients with DH demonstrate circulating IgA antibodies against epidermal transglutaminase (eTG) and tissue transglutaminase (tTG). It has been suggested that eTG is the autoantigen of DH. OBJECTIVE The purpose of this study was to characterize the autoimmune response to eTG and tTG in patients with DH on a normal or gluten-free diet (GFD). METHODS Sera from 52 patients with DH were studied for the presence of IgA antibodies to eTG and tTG by enzyme-linked immunosorbant assay. In 38 patients, serum was obtained before initiation of a GFD, whereas 14 patients had been on a GFD for at least 2 years. RESULTS Autoantibodies against eTG were detected in 36 of 38 patients (95%) and those against tTG in 30 of 38 patients (79%) with DH on a normal diet. Of 14 patients on a long-term GFD, 7 patients were free of DH lesions and did not require dapsone treatment. None of these patients showed circulating antibodies against eTG or tTG. The remaining 7 patients on a GFD were not able to stop taking dapsone. All these patients demonstrated anti-eTG antibodies, whereas only 3 of them showed additional reactivity against tTG. LIMITATION Autoantibody levels against eTG and tTG before and after introduction of a GFD were not examined in the same patients. CONCLUSION Our data suggest that antibodies to eTG are the most sensitive serologic marker in treated and untreated patients with DH and confirm the central role of eTG in the pathogenesis of this disease.

Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases

Despite the use of high‐dose systemic corticosteroids in combination with other immunosuppressants, in some patients with autoimmune bullous diseases only insufficient improvement is achieved. In these cases and in acute severe disease, adjuvant immunoapheresis has been increasingly used. A consensus meeting was held in mid‐2005 in Hamburg, aiming at developing guidelines for the use of immunoapheresis in the treatment of autoimmune bullous diseases.This paper summarizes the experts‘ recommendations.

Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of 23 patients

Background  It has been previously shown in a relatively small group of patients that a combination of immunoadsorption (IA) and rituximab with daily use of high‐dose oral corticosteroids and azathioprine/mycophenolate mofetil may induce a rapid and durable remission in severe, treatment‐resistant pemphigus.

Histopathology of anti-p200 pemphigoid.

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by circulating and tissue-bound antibodies against a 200-kd glycoprotein (p200) of the human dermis. We reviewed 10 lesional biopsies from seven patients with anti-p200 pemphigoid in an attempt to define typical histopathologic features of this disease. All biopsy specimens showed subepidermal blistering and a moderate to dense inflammatory infiltrate in the upper dermis. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. The inflammatory infiltrate was composed almost exclusively of neutrophils in six biopsies and contained a mixture of neutrophils and eosinophils in the remaining four. In three specimens, microabscess formation in the papillary dermis adjacent to the blister cavity was noted. Neutrophilic and eosinophilic spongiosis was found in five and three biopsies, respectively. We conclude that histopathology of anti-p200 pemphigoid is characterized by subepidermal blistering and a superficial inflammatory infiltrate, which is usually dominated by neutrophils but occasionally contains significant numbers of eosinophils. While this microscopic picture mimics that of linear IgA disease, dermatitis herpetiformis, or bullous pemphigoid, it should also alert a histopathologist to the possibility of anti-p200 pemphigoid and prompt immunofluorescence and immunoblotting studies for definite diagnosis or exclusion of this autoimmune subepidermal blistering disease.

Pemphigoid gestationis: new insights into the pathogenesis lead to novel diagnostic tools

Pemphigoid gestationis (PG), previously referred to as herpes gestationis, is an autoimmune disease of pregnancy and the early postpartum period. It is not related to herpes virus infection; the old term rather reflects the occurence of herpetiform lesions as a part of the clinical picture. Table 1 summarises the major autoimmune blistering diseases subdivided into those with intraand subepidermal split formation. PG belongs to the group of autoimmune subepidermal blistering diseases. Reports on the incidence of the disease range from 1:1700 to 1:50,000 pregnancies. More recent studies tend to provide higher estimates; this is most probably due to the development of more sensitive techniques for the diagnosis of PG.

Histopathology of anti-laminin 5 mucous membrane pemphigoid

BACKGROUND Anti-laminin 5 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against the major basement membrane component laminin 5 (laminin 332, epiligrin). OBJECTIVE AND METHODS We reviewed 17 biopsy specimens from 9 patients with anti-laminin 5 MMP in an attempt to define typical histopathologic features of the disease. RESULTS Fifteen specimens showed subepidermal blister formation, while two biopsy specimens revealed an epithelial ulcer. In 11 biopsies a sparse to moderate inflammatory infiltrate composed of lymphocytes and neutrophils with some eosinophils was observed. Four biopsies showed a dense infiltrate dominated by neutrophils in two cases and by eosinophils in one case. The remaining biopsy revealed a dense lymphoplasmacellular infiltrate without granulocytes. Scarring of the upper dermis was present only in 5 specimens. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. LIMITATIONS The number of patients studied was relatively small. CONCLUSIONS Histopathology of anti-laminin 5 MMP is characterized by subepidermal blistering and a sparse to moderate superficial lymphohistiocytic infiltrate with neutrophils and/or eosinophils. Both infiltrate density and composition may vary, making anti-laminin 5 MMP indistinguishable from other autoimmune subepidermal blistering diseases by histopathology alone. Scarring is present only in a minority of cases and is not a sensitive clue to the diagnosis of anti-laminin 5 MMP.

Trichoadenoma of Nikolowski is a distinct neoplasm within the spectrum of follicular tumors

BACKGROUND Trichoadenoma is a rare benign follicular tumor first described by Nikolowski 50 years ago. Both trichoadenoma and desmoplastic trichoepithelioma are composed of cords of epithelial cells and cornifying cysts embedded in sclerotic stroma. In trichoadenoma the cystic component predominates, while desmoplastic trichoepithelioma is a mostly solid neoplasm. Therefore trichoadenoma was suggested to represent a cystic variant of desmoplastic trichoepithelioma. OBJECTIVE The aim of this study was to investigate whether the morphologic overlap between trichoadenoma and desmoplastic trichoepithelioma translates into a similar immunohistochemical profile. METHODS We studied 19 trichoadenomas and 21 desmoplastic trichoepitheliomas for cytokeratin 20, Ber-EP4, and androgen receptor expression. RESULTS Eighteen of 19 trichoadenomas and all desmoplastic trichoepitheliomas demonstrated the presence of Merkel cells as detected by a monoclonal antibody against cytokeratin 20. In contrast, while all desmoplastic trichepitheliomas were positive for Ber-EP4, only 4 of 19 trichoadenomas showed any kind of reactivity for this marker. None of the trichoadenomas or desmoplastic trichoepitheliomas expressed androgen receptor. LIMITATIONS This study is limited by the moderate number of these rare tumors available for immunohistochemical analysis. CONCLUSION Our data demonstrate that trichoadenoma typically retains cytokeratin 20-positive Merkel cells but lacks Ber-EP4 and androgen receptor expression. Trichoadenoma is a distinct follicular tumor related but not identical to desmoplastic trichoepithelioma.