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SnapshotDx Quiz: February 2018

      What is Your Diagnosis?

      Figure 1
      Figure 1
      Images credit to University of Texas Southwestern Medical Center. The image is published with the patient’s permission.
      Editorial note: Welcome to the Journal of Investigative Dermatology (JID) SnapshotDx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image found below, while additional questions concern the findings reported in a JID article by Scholtissek et al. (https://doi.org/10.1016/j.jid.2017.03.018).
      Detailed answers and a list of relevant references are available following the Quiz Questions below.

      Quiz Questions

      QUESTIONS

      • 1.
        A 30-year old female presents with alopecia over three years. You observe erythematous annular plaques with scarring alopecia and follicular plugging on the scalp. What is your diagnosis?
        • a.
          Lichen planopilaris
        • b.
          Folliculitis decalvans
        • c.
          Discoid lupus erythematosus
        • d.
          Alopecia areata
        • e.
          Central centrifugal cicatricial alopecia
      • 2.
        Which of the following regarding cutaneous lupus erythematosus (CLE) is true?
        • a.
          Subacute cutaneous lupus erythematosus (SCLE) is primarily associated with a positive anti-Smith antibody.
        • b.
          The pathology of CLE is characterized by a perifollicular lymphocytic infiltrate and interface dermatitis, with absence of inflammation around dermal blood vessels.
        • c.
          Lesional inflammation in CLE is associated with expression of type I interferons and their inducible proteins (e.g. CXCL9/CXCL10).
        • d.
          Up to 80% patients with CLE can later progress to systemic lupus erythematosus (SLE).
        • e.
          The first line treatment for CLE includes oral antibiotics.
      • 3.
        Which of the following is a proposed mechanism by which keratinocytes play a role in the inflammatory response seen in CLE in the article by Scholtissek et al?
        • a.
          Keratinocytes produce IFN-regulated cytokines (CXCL10) in response to endogenous nucleic acids, thus driving the recruitment of CXCR3+ cells.
        • b.
          Keratinocytes take up external antigens via endocytosis and present it to T cells via MHC Class II molecules.
        • c.
          Keratinocytes release histamine to the local environment in response to external stimuli, such as UV irradiation, thus augmenting the inflammatory response.
        • d.
          Lysosomal-mediated autophagy of keratinocytes stimulates the production of CXCL10 by neighboring keratinocytes.
        • e.
          UVB radiation causes CC to TT transition mutations in CLE keratinocytes that favor keratinocyte apoptosis and subsequent activation of the innate immune response.
      See following pages for detailed answers.

      Detailed Answers

      QUESTIONS

      • 1.
        A 30-year old female presents with alopecia over three years. You observe erythematous annular plaques with scarring alopecia and follicular plugging on the scalp. What is your diagnosis?
      ANSWER: C. Discoid lupus erythematosus
      Explanation:
      The physical exam findings and the H&E image are most consistent with discoid lupus erythematosus (DLE), which is the most common subtype of cutaneous lupus erythematosus (CLE). DLE has a predilection for the scalp, face and ears. The lesions of DLE are typically disk-shaped erythematous to violaceous plaques with overlying scale and central atrophy. On the scalp, follicular plugging can be appreciated and can lead to a pattern of scarring alopecia. This H&E slide image shows several features that are consistent with DLE. The most prominent histological features of DLE are vacuolization of the basal layer (otherwise known as interface dermatitis), a dense periadnexal and perivascular lymphohistiocytic infiltrate, follicular keratin plugging, thickening of the basement membrane, and mucin deposition (
      • Elman S.A.
      • Joyce C.
      • Nyberg F.
      • Furukawa F.
      • Goodfield M.
      • Hasegawa M.
      • et al.
      Development of classification criteria for discoid lupus erythematosus: Results of a Delphi exercise.
      ).
      Discussion of incorrect answers
      • a.
        Lichen planopilaris
      Lichen planopilaris (LPP) is another cause of primary cicatricial alopecia, however, it presents with multifocal areas of alopecia with perifollicular erythema and scale. In contrary to DLE, LPP lesional changes occur in the periphery of the patch of alopecia (
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology. [Philadelphia].
      ). The histology of LPP involves a band- like lymphocytic infiltrate that favors perifollicular areas, and interface dermatitis may be present. However, LPP does not typically have a perivascular and perieccrine lymphocytic infiltrate, and mucin deposition is not seen (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: Lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      ).
      • b.
        Folliculitis decalvans
      Folliculitis decalvans is a highly inflammatory chronic pustular eruption in the scalp that results in permanent scarring alopecia. Late lesions may present as oval patches of alopecia with pustules at the margins. Unlike DLE, the inflammatory infiltrate of folliculitis decalvans is rich in neutrophils and it is mainly located around the follicle, sometimes extending into the follicle well (
      • Otberg N.
      • Kang H.
      • Alzolibani A.A.
      • Shapiro J.
      Folliculitis decalvans.
      ).
      • d.
        Alopecia areata
      Alopecia areata (AA) is a non-scarring alopecia that arises from T-cell driven autoimmunity against the hair follicles. It presents as round to oval patches of hair loss with broken-off terminal hairs present at the margins. Unlike DLE, the alopecia in AA does not lead to scarring and is reversible (
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology. [Philadelphia].
      ). Histologically, the hallmark feature of alopecia areata is miniaturization of the hair follicles, resulting in a complete absence of terminal hairs and a terminal:vellus hair ratio of 1:1. The inflammatory infiltrate in AA centers around the hair bulb, but this feature is variable across specimens. Eosinophils may also be present within the peribulbar infiltrate, which helps distinguish this condition from trichotillomania (
      • Busam K.J.
      Dermatopathology.
      ).
      • e.
        Central centrifugal cicatricial alopecia
      Central centrifugal cicatricial alopecia (CCCA) is another type of primary cicatricial alopecia with lymphocyte-associated inflammation. In CCCA, the alopecic patch is located on the vertex of the scalp and progresses symmetrically in a centrifugal pattern (
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology. [Philadelphia].
      ). Histologically, early CCCA is characterized by premature desquamation of the inner root sheath as well as a perifollicular lymphocytic infiltrate; however CCCA lacks the vacuolar interface dermatitis seen in LPP and DLE. As lesions progress to the late stage, the follicular epithelium is destroyed and replaced by connective tissue (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: Other lymphocytic primary cicatricial alopecias and neutrophilic and mixed primary cicatricial alopecias.
      ).
      • 2.
        Which of the following regarding cutaneous lupus erythematosus (CLE) is true?
      ANSWER: C. Lesional inflammation in CLE is associated to expression of type I interferons and their inducible proteins (e.g. CXCL9/CXCL10).
      Explanation:
      The functional model of CLE pathogenesis involves genetic and environmental factors (UV radiation, medications, and chemicals) that are able to trigger keratinocyte apoptosis and lead to an inflammatory cascade at the lesional level (
      • Kuhn A.
      • Wenzel J.
      • Weyd H.
      Photosensitivity, Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review.
      ). Central to this model is the production of type I interferons by plasmacytoid dendritic cells and keratinocytes, which in turn induce the expression of pro- inflammatory cytokines (CXCL9/CXCL10) and lead to the recruitment of CXCR3+ T cells (
      • Kirchhof M.G.
      • Dutz J.P.
      The Immunopathology of Cutaneous Lupus Erythematosus. Rheumatic Disease Clinics of.
      ). A positive feedback loop is generated from the interplay of these cytokines and the various cells of the immune system.
      Discussion of incorrect answers
      • a.
        Subacute cutaneous lupus erythematosus (SCLE) is primarily associated with a positive anti-Smith antibody
      SCLE is primarily associated with the presence of anti-Ro (SS-A) antibodies. Sontheimer et al were the first to demonstrate this association in 1982 (
      • Deng J.-S.
      • Sontheimer R.D.
      • Gilliam J.N.
      Relationships between antinuclear and anti-Ro/SS-A antibodies in subacute cutaneous lupus erythematosus.
      ,
      • Sontheimer R.D.
      • Maddison P.J.
      • Reichlin M.
      • Jordon R.E.
      • Stastny P.
      • Gilliam J.N.
      SErologic and hla associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus.
      ). Since then, multiple retrospective and cohort studies have shown this association (
      • Biazar C.
      • Sigges J.
      • Patsinakidis N.
      • Ruland V.
      • Amler S.
      • Bonsmann G.
      • et al.
      Cutaneous lupus erythematosus: First multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE).
      ,
      • Lee L.A.
      • Roberts C.M.
      • Frank M.
      • McCubbin V.R.
      • Reichlin M.
      The autoantibody response to ro/ssa in cutaneous lupus erythematosus.
      ). The median prevalence of anti-Ro (SS-A) antibodies in SCLE is estimated to be 50% (
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology. [Philadelphia].
      ). Recently, a retrospective review of 90 SCLE patients at Mayo Clinic found that 99% of the cohort was positive for anti-Ro (SS-A) autoantibodies measured by multiplex flow immunoassay (
      • Alniemi D.T.
      • Gutierrez A.
      • Drage L.A.
      • Wetter D.A.
      Subacute Cutaneous Lupus Erythematosus: Clinical Characteristics, Disease Associations, Treatments, and Outcomes in a Series of 90 Patients at Mayo Clinic, 1996-2011.
      ). In contrast, none of the patients in this cohort were positive for anti-Smith antibodies.
      • b.
        The pathology of CLE is characterized a perifollicular lymphocytic infiltrate and interface dermatitis, with absence of inflammation around dermal blood vessels.
      The inflammatory infiltrate in cutaneous lupus is composed of lymphocytes and histiocytes, and is located in perivascular and periadnexal regions of the skin. Interface dermatitis (basal layer vacuolization) is an important feature of CLE. Other prominent features that favor the diagnosis of CLE are follicular keratin plugging, thickening of the basement membrane, epidermal thinning, and mucin deposition. The histology of LPP involves a band-like lymphocytic infiltrate that favors perifollicular areas, and interface dermatitis may be present. However, LPP does not typically have a perivascular and perieccrine lymphocytic infiltrate, and mucin deposition is not seen (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: Lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      ).
      • d.
        Up to 80% patients with CLE can later progress to systemic lupus erythematosus (SLE).
      Patients who first develop lupus limited to the skin (CLE) are at risk of developing systemic lupus. However, the risk of progression has been estimated to be between 5%-25% in various population studies of CLE (
      • Durosaro O.
      • Davis M.P.
      • Reed K.B.
      • Rohlinger A.L.
      Incidence of cutaneous lupus erythematosus, 1965-2005: A population-based study.
      ,
      • Grönhagen C.M.
      • Fored C.M.
      • Granath F.
      • Nyberg F.
      Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden.
      ,
      • Wieczorek I.T.
      • Propert K.J.
      • Okawa J.
      • Werth V.P.
      Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus.
      ). Furthermore, CLE patients who progress to SLE do so by meeting other mucocutaneous ACR criteria (photosensitivity, malar rash, discoid rash, oral ulcers) and positive serologies such as ANA (
      • Wieczorek I.T.
      • Propert K.J.
      • Okawa J.
      • Werth V.P.
      Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus.
      ).
      • e.
        The first line treatment for CLE includes oral antibiotics.
      The first line treatment for CLE depends on the severity and extent of the disease. For mild disease, topical steroids and immunomodulators as well as implementing a strict sun protection regimen is the first step in treatment. For moderate disease or disease refractory to topical agents, the first line systemic therapy includes low-dose corticosteroids and antimalarial medications. For severe disease unresponsive to several antimalarial medication classes and higher doses of corticosteroids, immunosupressants and immunomodulators can be used (
      • Hejazi E.Z.
      • Werth V.P.
      Cutaneous Lupus Erythematosus: An Update on Pathogenesis, Diagnosis and Treatment.
      ).
      • 3.
        Which of the following is a proposed mechanism by which keratinocytes play a role in the inflammatory response seen in CLE in the article by Scholtissek et al?
      ANSWER: A. Keratinocytes produce IFN-regulated cytokines (CXCL10) in response to endogenous nucleic acids, thus driving the recruitment of CXCR3+ cytotoxic immune cells.
      Explanation:
      Scholtissek et al showed in a series of experiments that DNA and RNA motifs are able to induce expression of CXCL10 from keratinocytes in a CLE-like pattern. Furthermore, in vitro studies showed that UV radiation induces translocation of nucleic acids from the nucleus to the cytoplasm of cells, and enhances the capacity of DNA to trigger expression of CXCL10 in keratinocytes. CXCL10 binds to its co-receptor CXCR3 in CD4+ and CD8+ T cells, thus recruiting the immune system cells to the site of injury (
      • Wenzel J.
      • Proelss J.
      • Wiechert A.
      • Zahn S.
      • Bieber T.
      • Tüting T.
      CXCR3-mediated recruitment of cytotoxic lymphocytes in lupus erythematosus profundus.
      ). The authors postulate that blocking pathogen recognition receptor pathways through nucleic acids by the use of kinase inhibitors shows a promising target for future therapy in CLE (
      • Klaeschen A.S.
      • Wenzel J.
      Upcoming therapeutic targets in cutaneous lupus erythematous.
      ).
      Discussion of incorrect answers
      • b.
        Keratinocytes take up external antigens via endocytosis and present it to T cells via MHC Class II molecules.
      Keratinocytes have been shown to present self-antigen via self-expressed MHC II class molecules in mouse models of graft-versus-host disease in the skin (
      • Kim B.S.
      • Miyagawa F.
      • Cho Y.-H.
      • Bennett C.L.
      • Clausen B.E.
      • Katz S.I.
      Keratinocytes function as accessory cells for presentation of endogenous antigen expressed in the epidermis.
      ), however, this was not the mechanism studied in the article by Scholtissek et al.
      • c.
        Keratinocytes release histamine to the local environment in response to external stimuli, such as UV irradiation, augmenting the inflammatory response
      Histamine released from epidermal keratinocytes has been shown to play a role in hormone-induced itching associated with pigmented cutaneous lesions in mice (
      • Shimizu K.
      • Andoh T.
      • Yoshihisa Y.
      • Shimizu T.
      Histamine Released from Epidermal Keratinocytes Plays a Role in α-Melanocyte–Stimulating Hormone-Induced Itching in Mice.
      ). However, this was not the mechanism proposed by Scholtissek et al by which keratinocytes induce inflammation in CLE.
      • d.
        Lysosomal-mediated autophagy of keratinocytes stimulates the production of CXCL10 by neighboring keratinocytes
      Autophagy mechanisms in keratinocytes are important for maintenance of keratinocyte differentiation homeostasis, melanin metabolism, and elimination of dysfunctional organelles and other pathogens (
      • Li L.
      • Chen X.
      • Gu H.
      The signaling involved in autophagy machinery in keratinocytes and therapeutic approaches for skin diseases.
      ). For example, overexpression of some inflammatory cytokines, cathelicidin/LL-37 and S100A7 (psoriasin) is related to inhibition of autophagy (
      • Salzer S.
      • Kresse S.
      • Hirai Y.
      • Koglin S.
      • Reinholz M.
      • Ruzicka T.
      • et al.
      Cathelicidin peptide LL-37 increases UVB- triggered inflammasome activation: possible implications for rosacea.
      ). However, this was not the mechanism proposed by Scholtissek et al by which keratinocytes induce inflammation in CLE.
      • e.
        UVB radiation causes CC to TT transition mutations in CLE keratinocytes that favor keratinocyte apoptosis and subsequent activation of the innate immune response
      UVB radiation induces photo-products in DNA that are potentially mutagenic, and if not repaired, can cause CC to TT transition mutations, also known as UVB “signature” mutations (
      • D’Orazio J.
      • Jarrett S.
      • Amaro-Ortiz A.
      • Scott T.
      UV Radiation and the Skin.
      ). These mutations have been found in genes involved in the pathogenesis of UV-induced skin cancers. However, these mutations have not been shown to play a role in CLE pathogenesis.

      Supplementary Material

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