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SnapshotDx Quiz: November 2017

      What is Your Diagnosis?

      Figure 1
      Figure 1
      Images credit to Susana Ruiz-Tagle, Skinmed Dermatologic Clinic, Santiago, Chile
      Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Snapshot Dx Quiz— In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image above, while additional questions concern the findings reported in a JID article by Yuan et al. (https://doi.org/10.1016/j.jid.2017.05.032).
      Detailed answers and a list of relevant references are available following the Quiz Questions below.

      Quiz Questions

      • 1.
        What is your diagnosis?
        • a.
          Discoid lupus erythematosus (DLE)
        • b.
          Pemphigus vulgaris (PV)
        • c.
          Dermatitis herpetiformis (DH)
        • d.
          Linear Ig A bullous dermatosis (LABD)
        • e.
          Bullous pemphigoid
      • 2.
        Which of the following answers is TRUE?
        • a.
          The anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris are not pathogenic.
        • b.
          In fogo salvagem the prevalence of antibodies against desmoglein 3 is high.
        • c.
          There is negative correlation between disease activity and antibody titers in most patients with pemphigus vulgaris.
        • d.
          The presence of autoantibodies to plakins is a characteristic feature of pemphigus foliaceus.
        • e.
          Paraneoplastic pemphigus is associated in the majority of cases with non- Hodgkin's lymphoma, chronic lymphocytic leukemia, and Castleman's disease.
      • 3.
        Which of the following answers is FALSE according to the article by Yuan et al.?
        • a.
          Lesional skin in pemphigus vulgaris contains desmoglein-specific B-cells which are capable of secreting desmoglein antibodies.
        • b.
          Lesional skin in pemphigus vulgaris contains only T/B lymphocytes and no IgG secreting CD138+ plasma cells.
        • c.
          A significantly higher proportion of CD4+IL-21+ T-cells is detected in pemphigus vulgaris lesions versus healthy skin.
        • d.
          CCL19 expression is markedly increased in pemphigus vulgaris lesions versus healthy skin as detected by real-time PCR analysis.
        • e.
          Antibody levels secreted from in vitro cultured cells from pemphigus vulgaris lesions have a positive correlation with Pemphigus Disease Area Index.
      See following pages for detailed answers.

      Detailed Answers

      • 1.
        What is your diagnosis?
      ANSWER: b. Pemphigus vulgaris (PV)
      Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease that can cause severe morbidity and major complications. IgG autoantibodies are formed against Desmoglein 3 and Desmoglein 1 which create loss of cell adhesion of keratinocytes or acantholysis. These intraepidermal blisters clinically manifest as flaccid bullae, erosions, and crusts affecting the mucosal surfaces, most commonly the oral mucosa, and can appear anywhere on the skin surface (
      • Venugopal S.S.
      • Murrell D.F.
      Diagnosis and clinical features of pemphigus vulgaris.
      ). The primary skin lesions are thin walled, fragile blisters that arise on normal appearing skin or an erythematous base. The easily ruptured blisters can have clear, turbid, or hemorrhagic fluid that form erosions partially covered with crust. The painful erosions seen on oral mucosa most commonly involve the buccal and palatine mucosa, but can extend into the throat causing difficulty swallowing and can extend beyond the vermilion border of the lip leading to hemorrhagic crust. Unusual presentations of PV include isolated crusted plaque on face or scalp, paronychia, foot ulcers, and dyshidrotic eczema (
      • Bolognia J.
      • Jorizzo J.
      • Schaffer J.
      Dermatology.
      ).
      Discussion of incorrect answers
      • a.
        discoid lupus erythematosus (DLE)
        Lupus erythematosus is a chronic, autoimmune, multifactorial disease with a variety of symptoms. Cutaneous lupus erythematosus (CLE) is on one end of the spectrum and systemic lupus erythematosus (SLE) is on the other end, although both can occur together (
        • Bolognia J.
        • Jorizzo J.
        • Schaffer J.
        Dermatology.
        ). Discoid lupus erythematosus (DLE) is the most common subtype of CLE, accounting for about 70-80% of all cases of CLE (
        • Durosaro O.
        • Davis M.D.
        • Reed K.B.
        • Rohlinger A.L.
        Incidence of cutaneous lupus erythematosus, 1965-2005: A population-based study.
        ). Clinical features include well- demarcated, red scaly, disk-like plaques on scalp, face and ears that may cause pigmentary changes, scarring, and hair loss. The disease is more common in females with a slight African American predominance (
        • Callen J.P.
        Cutaneous lupus erythematosus: a personal approach to management.
        ). An estimated 60-80% of cases are localized DLE in which lesions are limited to the head and the neck, compared to generalized DLE in which lesions can occur on any body surface (
        • Callen J.P.
        Cutaneous lupus erythematosus: a personal approach to management.
        ;
        • Vera-Recabarren M.A.
        • Garcia-Carrasco M.
        • Ramos-Casals M.
        • Herrero C.
        Comparative analysis of subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus: Clinical and immunological study of 270 patients.
        ).
      • c.
        dermatitis herpetiformis (DH)
        Dermatitis herpetiformis (DH) is a chronic pruritic autoimmune blistering disorder associated with gluten sensitive disorders that include celiac disease. DH most commonly affects patients of northern European descent and occurs with higher prevalence in men than women. The disease manifests as symmetric, clustered, pruritic papulo-vesicular eruptions involving the extensor surfaces of extremities, buttock, face, neck, and scalp (
        • Bolotin D.
        • Petronic-Rosic V.
        Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation.
        ). Due to the severe pruritus, intact vesicles are rare and appear as pinpoint erosions and excoriations. The lesions usually heal without scarring, although postinflammatory pigmentary alteration can occur (
        • Nicolas M.E.
        • Krause P.K.
        • Gibson L.E.
        • Murray J.A.
        Dermatitis herpetiformis.
        ).
      • d.
        linear IgA dermatosis (LABD)
        Linear IgA bullous dermatosis (LABD) is a rare autoimmune subepidermal bullous disorder. Most cases are idiopathic with an unclear etiology. There are also cases induced by drugs, infection, and malignancy (
        • Antiga E.
        • Caproni M.
        • Fabbri P.
        Linear immunoglobulin A bullous dermatosis: need for an agreement on diagnostic criteria.
        ). LABD can occur in children and adults. The lesions present as clusters of annular papules, urticarial plaques, and vesiculobullous eruptions on the trunk, extremities, face, scalp, and perineum. The majority of cases also have mucosal involvement (
        • Chan L.S.
        • Regezi J.A.
        • Cooper K.D.
        Oral manifesta-tions of linear IgA disease.
        ). The characteristic lesions are tense arciform bulla in a “crown of jewels” configuration (
        • Guide S.V.
        • Marinkovich M.P.
        Linear IgA bullous dermatosis.
        ).
      • e.
        bullous pemphigoid
        Bullous pemphigoid is a chronic autoimmune subepidermal blistering disease with autoantibodies against BP antigen 180 and or BP antigen 230 which comprise the hemidesmosome adhesion complex in the basement membrane (
        • Thoma-Uszynski S.
        • Uter W.
        • Schwietzke S.
        • Schuler G.
        • Borradori L.
        • Hertl M.
        Autoreactive T and B cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230.
        ). This condition most frequently affects the elderly population with a chronic course with spontaneous exacerbations with no gender or ethnic predilection. The early lesions can appear as pruritic urticarial papules and plaques that often progress to tense bulla most often on the abdomen, thighs and forearms (
        • Schmidt E.
        • della Torre R.
        • Borradori L.
        Clinical features and practical diagnosis of bullous pemphigoid.
        ). The clear fluid filled tense blisters are 1-4 cm in diameters that erode and crust over. They can be localized or extensive. They heal without scarring in most cases and as they heal milia can appear (
        • Bolognia J.
        • Jorizzo J.
        • Schaffer J.
        Dermatology.
        ).
      • 2.
        Which of the following answers is TRUE?
      ANSWER: e. Paraneoplastic pemphigus is associated in the majority of cases with non- Hodgkin's lymphoma, chronic lymphocytic leukemia, and Castleman's disease.
      Paraneoplastic pemphigus (PNP) is a rare and life threatening autoimmune blistering disease associated with an underlying malignancy that occurs in patients between the ages of 45 to 70 years but has also been described in children and adolescents (
      • Anhalt G.J.
      • Kim S.C.
      • Stanley J.R.
      • Korman N.J.
      • Jabs D.A.
      • Kory M.
      • et al.
      Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia.
      ;
      • Czernik A.
      • Camilleri M.
      • Pittelkow M.R.
      • Grando S.A.
      Paraneoplastic autoimmune multiorgan syndrome: 20 years after.
      ). Clinical manifestation can include severe stomatitis and unlike other pemphigus can affect other types of epithelia, such as gastrointestinal and respiratory tract (
      • Nguyen V.T.
      • Ndoye A.
      • Bassler K.D.
      • Shultz L.D.
      • Shields M.C.
      • Ruben B.S.
      • et al.
      Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus.
      ). Thus, it often mimics features of drug reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis. Majority of cases are associated with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, Castleman’s disease, Waldenstrom’s macroglobulinemia, and thymoma. (
      • Nikolskaia O.V.
      • Nousari C.H.
      • Anhalt G.J.
      Paraneoplastic pemphigus in association with Castleman’s disease.
      ;
      • Anhalt G.J.
      Paraneoplastic pemphigus.
      ). Work up should include trying to find the underlying tumor, skin biopsies, and serum immunological studies (
      • Nguyen V.T.
      • Ndoye A.
      • Bassler K.D.
      • Shultz L.D.
      • Shields M.C.
      • Ruben B.S.
      • et al.
      Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus.
      ). PNP is characterized by the presence of autoantibodies against antigens such as desmoplakin I (250 kD), bullous pemphigoid antigen I (230 kD), desmoplakin II (210 kD), envoplakin (210 kD), periplakin (190 kD), plectin (500 kD), and a 170 kD protein (
      • Anhalt G.J.
      Paraneoplastic pemphigus.
      ).
      Discussion of incorrect answers
      • a.
        The anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris are not pathogenic.
        PV patients have circulating autoantibodies that are pathogenic. Seminal research proving this link was done via passive transfer studies in which IgG isolated from patients sera were injected into neonatal mice and induced ancantholysis and classic features seen in humans (
        • Anhalt G.J.
        • Labib R.S.
        • Voorhees J.J.
        • Beals T.F.
        • Diaz L.A.
        Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease.
        ). Both, Anti-Dsg 3 and Anti- Dsg 1 autoantibodies in PV have been shown to be pathogenic (
        • Amagai M.
        • Karpati S.
        • Prussick R.
        • Klaus-Kovtun V.
        • Stanley J.R.
        Autoantibodies against the amino- terminal cadherin binding domain of pemphigus vulgaris are pathogenic.
        ;
        • Ding X.
        • Diaz L.A.
        • Fairley J.A.
        • Giudice G.J.
        • Liu Z.
        The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic.
        ).
      • b.
        In fogo salvagem the prevalence of antibodies against desmoglein 3 is high.
        Pemphigus foliaceus is a blistering autoimmune skin disease with antibodies against desmoglein 1. There are several subtypes including fogo salvagem, which refers to an endemic form thought to be due to an environmental cause. Fogo salvagem was first reported in Brazil and has been reported in Colombia and Tunisia (
        • Diaz L.A.
        • Sampaio S.
        • Rivitti E.
        • Martins C.
        • Cunha P.
        • Lombardi C.
        • Almeida F.
        • Castro R.
        • Macca M.
        • Lavrado C.
        Endemic pemphigus foliaceus (fogo selvagem). Current and historic epidemiologic studies.
        ). A study focusing on communities in Brazil found that 98% of patients with fogo selvagem and up to 55% of normal subjects had anti-Dsg1 antibodies compared to up to 2% of normal subjects from the United States and Japan. In conclusion, there is a high prevalence of anti-Dsg1 antibodies amongst the population in endemic areas and the production of these antibodies is probably due to an unknown environmental exposure (
        • Warren S.J.
        • Lin M.S.
        • Giudice G.J.
        • Hoffmann R.G.
        • Hans-Filho G.
        • Aoki V.
        • Rivitti E.A.
        • Santos V.
        • Diaz L.A.
        The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.
        ).
      • c.
        There is negative correlation between disease activity and antibody titers in most patients with pemphigus vulgaris.
        A review of 20 cases of patients with PV found a statistically significant positive correlation between disease activity and antibody titers. They also found changes in titers associated with change in disease activity. However, serial titers were not precise enough to be used as a biomarker to guide therapy or prognosis in PV (
        • Fitzpatrick R.E.
        • Newcomer V.D.
        The correlation of disease activity and antibody titers in pemphigus.
        ).
      • d.
        The presence of autoantibodies to plakins is a characteristic feature of pemphigus foliaceus.
        Pemphigus foliaceus is characterized by the presence of autoantibodies to desmoglein 1 (
        • Amagai M.
        • Hashimoto T.
        • Green K.J.
        • Shimuzu N.
        • Nishikawa T.
        Antigen specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus.
        ). Serum antibodies to plakins, including desmoplakin I and II, envoplakin and periplakin are seen in association with paraneoplastic pemphigus (PNP). PNP is a mucocutaneous blistering disease that is most commonly associated with lymphoproliferative disorders (
        • Anhalt G.J.
        Paraneoplastic pemphigus.
        ).
      • 3.
        Which of the following answers is FALSE according to the article by Yuan et al.?
      ANSWER: b. Lesional skin in pemphigus vulgaris contains only T/B lymphocytes and no IgG secreting CD138+ plasma cells.
      Yuan et al. found that PV skin lesions have presence of CD3+, CD4+ T cells, CD19+ B cells and CD138+ plasma cells via immunohistochemistry and immunofluorescence (2017). This was performed to determine which immune cells are involved in providing an environment for antibody production, allow for tertiary lymphoid organ like structures, B-cell differentiation, and maturation.
      Discussion of incorrect answers (Statements that are TRUE)
      • a.
        Lesional skin in pemphigus vulgaris contains desmoglein-specific B-cells which are capable of secreting desmoglein antibodies.
        Yuan et al. examined cells from the skin with PV lesions and skin from healthy donors via flow cytometry assay. The assay showed that the frequency of CD19+ B cells was much higher in PV lesions than in healthy skin [(4.27 ± 1.13) % vs. (0.61 ± 0.31) %; P=0.0002]. Enzyme linked immunospot assay comparing PV and bullous pemphigoid revealed that the frequencies of Dsg1 and Dsg3-specific IgG secreting lymphocytes isolated from lesional PV skin were 0.22±0.031 % and 0.54 ±0.095 % respectively, while almost no Dsg1/3-specific IgG secreting cell was detected from bullous pemphigoid lesions. This suggests that the lymphocytes and Dsg specific B cells penetrate the lesional skin of PV pt and these B cells can secrete anti-Dsg antibodies (2017).
      • c.
        A significantly higher proportion of CD4+IL-21+ T-cells is detected in pemphigus vulgaris lesions versus healthy skin.
        A recent publication showed that circulating Follicular Helper T cells (Tfh), defined as CD4+CXCR5+ T cells, have been reported considerably elevated in pemphigus along with elevated IL-21 in plasma (
        • Hennerici T.
        • Pollmann R.
        • Schmidt T.
        • Seipelt M.
        • Tackenberg B.
        • Möbs C.
        • Ghoreschi K.
        • Hertl M.
        • Eming R.
        Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus.
        ). IL-21 had shown association with Tfh cells thus, the authors wanted to evaluate the association with CD4+ T cells. Flow cytometry comparing PV lesions versus healthy skin showed significantly higher proportion of CD4+IL-21+ T-cells in PV lesions [(3.98 ±0.87) % vs. control (1.21 ± 0.06) %; P=0.0195]. In addition, 47.87±7.803 % of IL-21 secreting CD4+ T cells did also produce IL-17a. Conversely, IL-21 negative CD4+ T cells secreted minimal level of IL-17a [(3.327 ±0.277) %, P=0.0294] (
        • Yuan H.
        • Zhou S.
        • Liu Z.
        • Cong W.
        • Fei X.
        • Zeng W.
        • Zhu H.
        • Xu R.
        • Wang Y.
        • Zheng J.
        • Pan M.
        Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis.
        ).
        IL-17 has been demonstrated to play a crucial role in initiating and controlling ectopic lymphoid neogenesis (
        • Grogan J.L.
        • Ouyang W.
        A role for Th17 cells in the regulation of tertiary lymphoid follicles.
        ). These results indicate that CD4+ T cells may promote B cells for antibody production in pemphigus lesions, and are associated with IL-21 secreting T helper cells that are capable of IL-17a production (
        • Yuan H.
        • Zhou S.
        • Liu Z.
        • Cong W.
        • Fei X.
        • Zeng W.
        • Zhu H.
        • Xu R.
        • Wang Y.
        • Zheng J.
        • Pan M.
        Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis.
        ).
      • d.
        CCL19 expression is markedly increased in pemphigus vulgaris lesions versus healthy skin as detected by real-time PCR analysis.
        CCL19 expression has been shown to participate in the process of lymphoid tissue formation (
        • van de Pavert S.A.
        • Mebius R.E.
        New insights into the development of lymphoid tissues.
        ). The authors validated this gene by real time PCR analysis to confirm microarray data. CCL19 was significantly upregulated at the transcriptional level, and increased by more than 4.0 folds in PV versus healthy controls (P=0.0378). Per the authors, this suggests the role of CCL19 in aggregation of T/B lymphocytes (
        • Yuan H.
        • Zhou S.
        • Liu Z.
        • Cong W.
        • Fei X.
        • Zeng W.
        • Zhu H.
        • Xu R.
        • Wang Y.
        • Zheng J.
        • Pan M.
        Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis.
        ).
      • e.
        Antibody levels secreted from in vitro cultured cells from pemphigus vulgaris lesions have a positive correlation with Pemphigus Disease Area Index.
        In vitro cultures of both anti-Dsg1 and Dsg3 antibodies from pemphigus vulgaris lesions had a positive correlation with the Pemphigus Disease Area Index (PDAI) (P=0.0206, R=0.683 and P=0.0159, R=0.676, respectively). The frequency of CD19+ B cells infiltrating PV lesions also had a positive correlation to PDAI. According to Yuan et al. these results support that B cells from PV lesions are able to secrete anti-Dsg1 and anti-Dsg 3 antibodies.

      Supplementary Material

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