SnapshotDx Quiz: October 2021

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 shown, while additional questions concern the findings reported in the JID article by Patel et al. (2021) (https://doi.org/10.1016/j.jid.2021.02.748). Detailed answers and a list of relevant references are available following the Quiz Questions below. 1.A 45-year-old Caucasian female presents with erythematous to violaceous papules and plaques over the extensor surfaces of metacarpophalangeal and interphalangeal joints for 6 months (Figure 1). The patient also complains of symmetric and proximal muscle weakness in arms and legs and has recently noticed difficulty washing her hair. What is the diagnosis?a.Subacute cutaneous lupus erythematosusb.Allergic contact dermatitisc.Dermatomyositis (DM)d.Psoriasise.Lichen planus2.According to the paper by Patel et al. (2021), which cells correlated positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores?a.FOXP3+ T cellsb.CD8+ T cellsc.Plasmacytoid dendritic cells (DCs)d.Myeloid DCse.CD14+ macrophages3.What is a potential therapeutic target the authors propose may be important for DM?a.Peroxisome proliferator‒activated receptor-γb.TNF-αc.FGFRd.LXR-αe.IL-23 See following pages for detailed answers 1.A 45-year-old Caucasian female presents with erythematous to violaceous papules and plaques over the extensor surfaces of metacarpophalangeal and interphalangeal joints for 6 months (Figure 1). The patient also complains of symmetric and proximal muscle weakness in arms and legs and has recently noticed difficulty washing her hair. What is the diagnosis?CORRECT ANSWER: c. Dermatomyositis (DM)These skin findings describe Gottron’s papules seen in DM. DM is a chronic autoimmune disorder of the skin and muscles with a limited understanding of its pathogenesis. Characteristic skin involvement includes Gottron’s papules, which consists of erythematous papules and plaques over dorsal knuckles, and shawl sign, which presents as poikilodermatous plaques on the upper back, posterior neck, and shoulders (Marvi et al., 2012Marvi U. Chung L. Fiorentino D.F. Clinical presentation and evaluation of dermatomyositis.Indian J Dermatol. 2012; 57: 375-381Crossref PubMed Scopus (43) Google Scholar). The pathogenesis of DM is thought to be related to abnormal signaling of the IFN pathway (Huard et al., 2017Huard C. Gullà S.V. Bennett D.V. Coyle A.J. Vleugels R.A. Greenberg S.A. Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis.Br J Dermatol. 2017; 176: 1224-1230Crossref PubMed Scopus (52) Google Scholar; Kao et al., 2011Kao L. Chung L. Fiorentino D.F. Pathogenesis of dermatomyositis: role of cytokines and interferon.Curr Rheumatol Rep. 2011; 13: 225-232Crossref PubMed Scopus (36) Google Scholar). Patients with classic DM (CDM) present with proximal and symmetric muscle weakness such as this patient. For patients with CDM, muscle symptoms may present shortly before, after, or at the same time as skin manifestations (Marvi et al., 2012Marvi U. Chung L. Fiorentino D.F. Clinical presentation and evaluation of dermatomyositis.Indian J Dermatol. 2012; 57: 375-381Crossref PubMed Scopus (43) Google Scholar). About 20% of patients with DM have a skin-predominant phenotype without clinical signs of muscle weakness known as amyopathic DM (Bendewald et al., 2010Bendewald M.J. Wetter D.A. Li X. Davis M.D. Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota.Arch Dermatol. 2010; 146: 26-30Crossref PubMed Scopus (173) Google Scholar).Discussion of incorrect answers:a.Subacute cutaneous lupus erythematosus: Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease with highly variable clinical manifestations, which may occur in the context of systemic lupus erythematosus or without other organ involvement (Gilliam and Sontheimer, 1981Gilliam J.N. Sontheimer R.D. Distinctive cutaneous subsets in the spectrum of lupus erythematosus.J Am Acad Dermatol. 1981; 4: 471-475Abstract Full Text PDF PubMed Scopus (355) Google Scholar). As a subtype of CLE, subacute cutaneous lupus erythematosus (SCLE) presents with erythematous macules and papules that develop into papulosquamous or annular plaques. The lesions are often photosensitive and can appear on the V area of the neck and upper chest, back, or arms (Rothfield et al., 2006Rothfield N. Sontheimer R.D. Bernstein M. Lupus erythematosus: systemic and cutaneous manifestations.Clin Dermatol. 2006; 24: 348-362Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). The pathogenesis of SCLE is still being elucidated but is thought to be due to an interplay of genetics, environmental triggers, and immunologic factors, including the IFN-1 pathway (Braunstein et al., 2012Braunstein I. Klein R. Okawa J. Werth V.P. The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score.Br J Dermatol. 2012; 166: 971-975Crossref PubMed Scopus (83) Google Scholar).b.Allergic contact dermatitis: Allergic contact dermatitis (ACD) is a T-cell–mediated type-IV hypersensitivity response to foreign allergens coming into contact with the skin. The clinical presentation of ACD includes erythematous scaly papules coalescing into plaques, often in a linear pattern. The mechanism of action is thought to be a two-phase process. The first phase begins with sensitization with an allergen or hapten that is presented by dendritic cells (DCs) to T cells, which then become effector T cells. In the elicitation phase when the allergen is reintroduced, these allergen-specific T cells then produce dermatitis, which develops around 72 hours after re-exposure to the allergen (Brar, 2021Brar K.K. A review of contact dermatitis.Ann Allergy Asthma Immunol. 2021; 126: 32-39Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar; Garzorz-Stark et al., 2018Garzorz-Stark N. Lauffer F. Krause L. Thomas J. Atenhan A. Franz R. et al.Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate TH17-deviated acute contact dermatitis in human subjects.J Allergy Clin Immunol. 2018; 141: 1320-1333.e11Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar).d.Psoriasis: Psoriasis is a chronic inflammatory skin disease that presents with characteristic cutaneous findings of well-demarcated erythematous, silvery, scaly plaques and papules on the scalp, elbows, knees, and lumbosacral areas. There are various forms of psoriasis such as plaque, pustular, and guttate psoriasis. Although the pathogenesis is not fully understood, psoriasis has been characterized as having defects in proliferation and differentiation of keratinocytes (KCs) involving aberrant T cells, DCs, and cytokines (Rendon and Schäkel, 2019Rendon A. Schäkel K. Psoriasis pathogenesis and treatment.Int J Mol Sci. 2019; 20: 1475Crossref Scopus (329) Google Scholar).e.Lichen planus: Lichen planus is an inflammatory skin condition that classically presents as pruritic, polygonal, violaceous papules and plaques. There are a wide variety of morphologies and affected locations. Lesions are generally symmetrically distributed, favoring the flexural surfaces of the forearms, wrists, and ankles; the dorsal surfaces of hands, shins, and trunk; and the sacral regions (Weston and Payette, 2015Weston G. Payette M. Update on lichen planus and its clinical variants.Int J Womens Dermatol. 2015; 1: 140-149Crossref PubMed Scopus (75) Google Scholar). Mucosal involvement may also be seen with cutaneous disease or as the only manifestation (Gorouhi et al., 2014Gorouhi F. Davari P. Fazel N. Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis.ScientificWorldJournal. 2014; 2014: 742826Crossref PubMed Scopus (175) Google Scholar). Pathogenesis is thought to be due to a type-1 immune response involving cytotoxicity of T cells and NK cells and destruction of KCs (Khan et al., 2003Khan A. Farah C.S. Savage N.W. Walsh L.J. Harbrow D.J. Sugerman P.B. Th1 cytokines in oral lichen planus.J Oral Pathol Med. 2003; 32: 77-83Crossref PubMed Scopus (172) Google Scholar).2.According to the paper by Patel et al. (2021), which cells correlated positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores?CORRECT ANSWER: e. CD14+ macrophagesIn this study, the authors sought to further characterize the pathogenesis of DM and the inflammatory infiltrate in skin lesions using a novel method of imaging mass cytometry to identify potential therapeutic targets at the cellular level. They found a diversity of monocyte‒macrophage populations in DM skin and found that the most common cells were macrophages and myeloid DCs, followed by T cells, whereas previous studies reported CD4+ T cells to be most populous (Caproni et al., 2004Caproni M. Torchia D. Cardinali C. Volpi W. Del Bianco E. D'Agata A. et al.Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis.Br J Dermatol. 2004; 151: 784-791Crossref PubMed Scopus (67) Google Scholar). They identified four distinct groups of monocyte‒macrophage populations, including CD14+ single-positive macrophages, CD14+ CD16+ macrophages, MAC387+ macrophages, and phosphorylated STING+ macrophages, that were increased in DM skin compared with those in the healthy controls. They also found that CD14+ single-positive macrophages correlated positively with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), a validated and widely used instrument to quantify cutaneous disease in DM (Anyanwu et al., 2015Anyanwu C.O. Fiorentino D.F. Chung L. Dzuong C. Wang Y. Okawa J. et al.Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing disease severity and assessing responsiveness to clinical change.Br J Dermatol. 2015; 173: 969-974Crossref PubMed Scopus (44) Google Scholar). This highlights the monocyte‒macrophage population as a potential therapeutic target for DM.Discussion of incorrect answers:a.FOXP3+ T cells: FOXP3+ T cells are T-regulatory cells responsible for the suppression of T-cell function and are required for maintaining immune tolerance and prevention of autoimmune disease (Li et al., 2015Li Z. Li D. Tsun A. Li B. FOXP3+ regulatory T cells and their functional regulation.Cell Mol Immunol. 2015; 12: 558-565Crossref PubMed Scopus (128) Google Scholar). Although this paper did find increased numbers of FOXP3+ cells in DM skin compared with that in healthy control skin, FOXP3+ T cells were not found to correlate with CDASI scores.b.CD8+ T cells: CD8+ T cells or cytotoxic T cells are critical in our immune defense system against intracellular pathogens and tumor surveillance by directly killing infected or cancerous cells by different mechanisms. This study found that CD8+ T cells were found in increased numbers in DM skin compared with those in healthy controls. However, CD8+ T cells were not found to be correlated with CDASI scores.c.Plasmacytoid DCs: Plasmacytoid DCs (pDCs) are a subset of DCs that are CD123+ and are known to produce IFN-α. They have been reported to be present in increased numbers in both DM and lupus erythematous skin samples (McNiff and Kaplan, 2008McNiff J.M. Kaplan D.H. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus.J Cutan Pathol. 2008; 35: 452-456Crossref PubMed Scopus (81) Google Scholar). This study at hand also found an increased number of pDCs in DM skin compared with that in the healthy skin and found an association between pDCs and IFN-γ. However, these cells were not found to correlate with CDASI scores.d.Myeloid DCs: Myeloid DCs (mDCs) are another subset of DCs that activate naive T cells, thus serving as the bridge between the adaptive and innate immune responses. mDCs were among the most common cells found in DM skin along with macrophages. This study showed that mDCs had a high expression of IFN-β on the basis of immunofluorescence stainings. In addition, the authors reported that mDCs in DM skin expressed IL-4 and the pro-itch cytokine IL-31 and correlated positively with skindex-29 itch question. However, mDCs were not found to correlate with CDASI scores.3.What is a potential therapeutic target the authors propose may be important for DM?CORRECT ANSWER: a. Peroxisome proliferator‒activated receptor-γPeroxisome proliferator‒activated receptor-γ (PPAR-γ) is a nuclear hormone receptor known to play a key role in inflammatory responses. The study at hand found that there was increased deactivated (phosphorylated) PPAR-γ in DM endothelial cells compared with those in healthy controls. Previous studies have reported that PPAR is a negative regulator of DC maturation and may lead to CD4 anergy (Klotz et al., 2007Klotz L. Dani I. Edenhofer F. Nolden L. Evert B. Paul B. et al.Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy.J Immunol. 2007; 178: 2122-2131Crossref PubMed Scopus (92) Google Scholar). In addition, increased amounts of inactivated phosphorylated PPAR-γ in DM may in turn assist mDC function, and decreased PPAR-γ signaling leads to increased recruitment of inflammatory cells (Mishra, 2017Mishra A. Metabolic plasticity in dendritic cell responses: implications in allergic asthma.J Immunol Res. 2017; 2017: 5134760Crossref PubMed Scopus (12) Google Scholar; Pasceri et al., 2000Pasceri V. Wu H.D. Willerson J.T. Yeh E.T. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators.Circulation. 2000; 101: 235-238Crossref PubMed Scopus (496) Google Scholar). Therefore, the study suggests that PPAR-γ agonists such as lenabasum may decrease the migration of inflammatory cells in DM and thus are potentially promising treatments in DM (Werth et al., 2019Werth V.P. Pearson D. Okawa J. Feng R. Concha J. Patel B. et al.Safety and efficacy of lenabasum in refractory skin-predominant dermatomyositis subjects treated on an open-label extension of trial JBT101-DM-001.J Invest Dermatol. 2019; 139: S105Abstract Full Text Full Text PDF Google Scholar).Discussion of incorrect answers:b.TNF-α: TNF-α is a cytokine involved in the homeostasis of the immune system. However, it also is involved in pathological processes of chronic inflammation, autoimmunity, and malignancies (Balkwill, 2006Balkwill F. TNF-alpha in promotion and progression of cancer.Cancer Metastasis Rev. 2006; 25: 409-416Crossref PubMed Scopus (569) Google Scholar) and have become a therapeutic target for many rheumatologic diseases. In dermatology, TNF-α inhibitors such as etanercept, infliximab, and adalimumab are approved for use in psoriasis and hidradenitis suppurativa (Sobell, 2016Sobell J.M. Update on TNF inhibitors in dermatology.Semin Cutan Med Surg. 2016; 35: S104-S106Crossref PubMed Scopus (2) Google Scholar). Although TNF-α may play a role in the pathogenesis of DM (Lundberg and Dastmalchi, 2002Lundberg I.E. Dastmalchi M. Possible pathogenic mechanisms in inflammatory myopathies.Rheum Dis Clin North Am. 2002; 28: 799-822Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar), it was not studied in this paper.c.FGFR: FGFR is a tyrosine kinase receptor that controls the development, repair, and disease of the skin and various other tissues (Meyer et al., 2011Meyer M. Müller A.K. Yang J. Ŝulcová J. Werner S. The role of chronic inflammation in cutaneous fibrosis: fibroblast growth factor receptor deficiency in keratinocytes as an example.J Investig Dermatol Symp Proc. 2011; 15: 48-52Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). It has been implicated in the pathogenesis of fibrotic diseases, such as systemic sclerosis, and is being investigated as a potential therapeutic target for fibrosis (Chakraborty et al., 2020Chakraborty D. Zhu H. Jüngel A. Summa L. Li Y.N. Matei A.E. et al.Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis.Sci Transl Med. 2020; 12: eaaz5506Crossref PubMed Scopus (9) Google Scholar). FGFR was not studied in this paper.d.LXR-α: LXR-αs are ligand-dependent nuclear receptors expressed in the liver, adipose tissue, tissue, intestines, kidney, macrophages, and skin. They are known to play key roles in lipid homeostasis and inflammatory responses (Bensinger and Tontonoz, 2008Bensinger S.J. Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors.Nature. 2008; 454: 470-477Crossref PubMed Scopus (618) Google Scholar; Chinetti-Gbaguidi and Staels, 2009Chinetti-Gbaguidi G. Staels B. Lipid ligand-activated transcription factors regulating lipid storage and release in human macrophages.Biochim Biophys Acta. 2009; 1791: 486-493Crossref PubMed Scopus (22) Google Scholar; Oosterveer et al., 2010Oosterveer M.H. Grefhorst A. Groen A.K. Kuipers F. The liver X receptor: control of cellular lipid homeostasis and beyond implications for drug design.Prog Lipid Res. 2010; 49: 343-352Crossref PubMed Scopus (55) Google Scholar). LXRs have been implicated in lupus-like autoimmunity and have been studied as therapeutic targets to decrease inflammatory cytokine production in lupus (Han et al., 2018Han S. Zhuang H. Shumyak S. Wu J. Xie C. Li H. et al.Liver X receptor agonist therapy prevents diffuse alveolar hemorrhage in murine lupus by repolarizing macrophages.Front Immunol. 2018; 9: 135Crossref PubMed Scopus (16) Google Scholar). LXRs were not discussed in this article.e.IL-23: IL-23 is a proinflammatory cytokine secreted by macrophages in DCs in peripheral tissues of the skin, intestinal mucosa, and lung (McKenzie et al., 2006McKenzie B.S. Kastelein R.A. Cua D.J. Understanding the IL-23-IL-17 immune pathway.Trends Immunol. 2006; 27: 17-23Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar). It is thought to lead to downstream effects of autoreactive IL-17‒producing T cells as well as chronic inflammation. It has been implicated in the pathogenesis of inflammatory bowel disease, psoriasis, rheumatoid arthritis, and multiple sclerosis (Tang et al., 2012Tang C. Chen S. Qian H. Huang W. Interleukin-23: as a drug target for autoimmune inflammatory diseases.Immunology. 2012; 135: 112-124Crossref PubMed Scopus (162) Google Scholar). IL-23 antagonists are being used to block the signaling and differentiation of cytokine production in these inflammatory diseases. However, IL-23 was not investigated in this paper.