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SnapshotDx Quiz: July 2016

  • Lucy Chen
    Affiliations
    Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida
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  • Mariya Miteva
    Correspondence
    Correspondence: Mariya Miteva, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Ave, RMSB 2023A, Miami, Florida 33136, USA.
    Affiliations
    Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida
    Search for articles by this author

      What is Your Diagnosis?

      Figure 1
      Figure 1
      Image is used with the permission of Anna Nichols, University of Miami.
      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 above, while additional questions concern the findings reported in a JID article by Cho et al. (http://dx.doi.org/10.1016/j.jid.2016.03.001).
      Detailed answers and a list of relevant references are available following the Quiz Questions below.

      Quiz Questions

      • 1.
        What is your diagnosis?
        • a.
          contact dermatitis
        • b.
          dermatomyositis
        • c.
          scleredema
        • d.
          psoriasis
        • e.
          acanthosis nigricans
      • 2.
        Which of the following answers is TRUE about dermatomyositis?
        • a.
          TGF-β2 expression is increased in cutaneous lesions of dermatomyositis and lupus erythematosus
        • b.
          Skin lesion severity has not been associated with relapsing disease course in dermatomyosistis
        • c.
          Combined treatment with prednisone and either cyclosporin or methotrexate is as effective as prednisone alone in juvenile dermatomyositis
        • d.
          Complement C5b-9 MAC is involved in the pathogenesis of dermatomyositis
        • e.
          The risk of malignancy in dermatomyositis remains equally high within the first 5 years of the diagnosis
      • 3.
        Which of the following answers is FALSE according to the article by Grace Cho et al.?
        • a.
          Functional analysis of the disease signature showed that Interferon (IFN) signaling is the most significantly altered pathway in dermatomyositis samples
        • b.
          Alpha-adrenergic agonists have a potent vasoconstrictor effect which has therapeutic value in dermatomyositis
        • c.
          STAT1 and IFIH1 are regulators of the IFN signaling
        • d.
          Topical alpha-adrenergic agonists have been used in the treatment of rosacea
        • e.
          Brimodine 0.33% gel failed to change the clinical appearance of facial and truncal erythema in patients with refractory cutaneous dermatomyositis
      See following pages for detailed answers.

      Detailed Answers

      • 1.
        What is your diagnosis?
      ANSWER: b)
      Dermatomyositis is an inflammatory autoimmune disease that presents with characteristic skin and muscle findings. The most important diagnostic feature of dermatomyositis is depicted here as poikiloderma, which is characterized by a photodistributed violaceous rash on the neck, chest and upper back (also known as the “shawl sign”). Often, these plaques can be very pruritic and demonstrate many excoriations. Other common cutaneous manifestations are periorbital edema with violaceous patches (heliotrope sign), erythematous lichenoid papules over the knuckles (Gottron’s papules), and nail fold changes (ragged cuticles and telangiectasias) (
      • Bolognia J.
      • Jorizzo Joseph L.
      • Schaffer Julie V.
      Dermatology.
      ). Systemic complaints initially begin as fatigue and malaise, followed by a distinctive myopathy of the proximal muscle groups. There is a significant association with occult malignancy in adults with dermatomyositis (reported from less than 10% to greater than 50%). Carcinomas of the colorectal and ovarian type are commonly represented, as well as breast, lung, gastric, pancreatic and lymphomas (
      • Hill C.L.
      • Zhang Y.
      • Sigurgeirsson B.
      • Pukkala E.
      • Mellemkjaer L.
      • Airio A.
      • et al.
      Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.
      ).
      Discussion of incorrect answers
      • a)
        Contact dermatitis is a pruritic eczematous reaction to an external agent that comes into contact with the skin. The most prevalent allergens are nickel, poison ivy, fragrance, and neomycin. Common presentations of allergic contact dermatitis are well-demarcated pruritic plaques on areas of the skin that make contact with the allergen. Occasionally, it can be a generalized eruption with ill-defined eczematous pruritic patches and plaques. A detailed history of patient’s exposures, occupation, and hobbies as well as skin patch testing to identify the causative allergen are the key components to making this diagnosis.
      • c)
        Scleredema is a rare condition characterized by diffuse induration of the skin due to increased deposition of mucin between dermal collagen bundles. There are three typical manifestations: 1. Acute course, following a respiratory tract infection 2. Chronic subtle course associated with monoclonal gammopathy and 3. Chronic course associated with diabetes. The usual location of scleredema is on the upper back and is readily diagnosed by the woody-type firmness of the face, neck, upper back and shoulders, without any superficial cutaneous changes. (
        • Beers W.H.
        • Ince A.
        • Moore T.L.
        Scleredema adultorum of Buschke: a case report and review of the literature.
        )
      • d)
        Psoriasis is one of the most prevalent skin conditions in the world (
        • Christophers E.
        Psoriasis--epidemiology and clinical spectrum.
        ). Its manifestations are readily identified as erythematous, micaceous scaly plaques on extensor surfaces and nail changes, though other forms (pustular, inverse, palmar plantar, annular, etc.) exist as well. Lesions can demonstrate the Koebner phenomenon, (appearing in areas after skin trauma) and range in size from papules to plaques, or potentially covering the entire body surface (erythroderma). Patients complain of itching, occasional tenderness, and pinpoint bleeding if the thicken silvery scale is lifted away.
      • e.)
        Acanthosis Nigricans presents as velvety, thickened plaques in intertriginous folds typically in an obese person. The posterior neck is a common location as well as axilla. It is a herald for metabolic endocrinopathies, namely insulin-resistant diabetes and polycystic ovarian syndrome. However in non-obese persons, it may represent a paraneoplastic process.(
        • Higgins S.P.
        • Freemark M.
        • Prose N.S.
        Acanthosis nigricans: a practical approach to evaluation and management.
        )
      • 2.
        Which of the following answers is TRUE about dermatomyositis?
      ANSWER: d)
      The complement system is integral to the pathogenesis of dermatomyositis. Immunochemical antibody studies were performed by Kissel et. al. to localize the C5b-9 membrane attack complex to the microvasculature of muscle biopsy specimens in adult and juvenile DM patients (
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      ). Control specimens did not demonstrate any deposition in this area. This study was integral to demonstrating that vessel injury in DM is mediated by complement deposition and activity. Later studies confirmed immunofluorescence of vascular C5-9 deposition in DM skin specimens (
      • Magro C.M.
      • Crowson A.N.
      The immunofluorescent profile of dermatomyositis: a comparative study with lupus erythematosus.
      ).
      Discussion of incorrect answers
      • a)
        DM and lupus erythematosus (LE) are both autoimmune conditions with similar clinical and histological features. Nakamura et al. found common and specific molecular pathways by proteomic analysis of DM and LE compared to control (normal subject) skin samples (
        • Nakamura K.
        • Jinnin M.
        • Kudo H.
        • Inoue K.
        • Nakayama W.
        • Honda N.
        • et al.
        The role of PSMB9 up-regulated by interferon signature in the pathophysiology of cutaneous lesions of dermatomyositis and lupus erythematosus.
        ). This molecular signature focuses on PSMB9, a target gene of interferon in epidermal keratinocytes. The hypothesis is that increased PSMB9 due to interferon signaling induces TGF-β2 and TGF-β3 to stimulate glycosaminoglycan synthesis. TGF-β3 expression was upregulated in both DM and LE, however only DM samples demonstrated TGF-β2 expression. This finding begins to establish a molecular signature to distinguish DM from LE skin features.
      • b)
        Vuong et al. conducted a retrospective study of DM patients in order to identify those factors most strongly associated with disease relapse (
        • Vuong V.
        • Duong T.A.
        • Aouizerate J.
        • Authier F.J.
        • Ingen-Housz-Oro S.
        • Valeyrie-Allanore L.
        • et al.
        Dermatomyositis: factors predicting relapse.
        ). Relapse was defined as recurrence of muscle or cutaneous disease after improvement leading to a change in systemic treatment regimen. Thirty-four patients with classic DM were identified from the clinical database. Patients with amyopathic, paraneoplastic and juvenile DM were excluded. By univariate analysis, two factors were significantly associated with relapse: dysphonia [HR 3.2 (1.2–8.5)] and severe skin involvement. [HR 3.5 (1.2–7.9)]. Skin involvement was scored by the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) that measures extent of disease activity such as erythema, scale, ulcerations as well as presence of poikiloderma, calcinosis, Gottron’s sign, periungual changes and alopecia (
        • Yassaee M.
        • Fiorentino D.
        • Okawa J.
        • Taylor L.
        • Coley C.
        • Troxel A.B.
        • et al.
        Modification of the Cutaneous Dermatomyositis Disease Area and Severity Index, an outcome instrument.
        ). It is important to identify these two factors at the time of presentation as these can predict a more aggressive or alternative treatment course.
      • a)
        Therapies for juvenile dermatomyositis are based on case series or anecdotal experience. Ruperto et al. (
        • Ruperto N.
        • Pistorio A.
        • Oliveira S.
        • Zulian F.
        • Cuttica R.
        • Ravelli A.
        • et al.
        Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.
        ) conducted a randomized trial of 139 juvenile DM patients treated with prednisone or prednisone in combination with cyclosporine or with methotrexate. The endpoints of the study measured were clinical improvement, time to remission, time to treatment failure and safety profile. The results demonstrated that combination treatment with prednisone plus either cyclosporine or methotrexate was superior to prednisone as monotherapy due to shorter time to clinical remission, shorter time to clinically inactive disease and greater time to treatment failure. Combination therapy also permitted faster time to prednisone discontinuation. However, patients in the prednisone plus cyclosporine group suffered greater adverse events such as gastrointestinal disorders, hypertrichosis, hirsutism and infections.
      • e)
        Chen et. al retrospectively examined the time course for DM patients to develop malignancies and the risk factors for developing these cancers (
        • Chen D.
        • Yuan S.
        • Wu X.
        • Li H.
        • Qiu Q.
        • Zhan Z.
        • et al.
        Incidence and predictive factors for malignancies with dermatomyositis: a cohort from southern China.
        ). The most common malignant disease in this cohort of 246 Chinese patients was nasopharyngeal carcinoma and ovarian carcinoma, then lung and colon. The majority (65%) occurred within the first year after DM diagnosis. The latest malignancy developing was at 35 months after diagnosis. By multivariate regression analysis, male gender, dysphagia and elevated ESR were risk factors for occurrence of malignancy. Malignancy screening within the first three years is prudent in an adult patient with newly diagnosed DM.
      • 3.
        Which of the following answers is FALSE according to the article by Grace Cho et al.?
      ANSWER: e)
      Based on comparison of the dermatomyositis signature genes to the molecular data from small molecules in DrugBank, oxymetazoline was selected as a potential candidate to have therapeutic value for DM. By CMap Drug-disease scoring, oxymetazoline was predicted to have a therapeutic effect, recorded at -0.219. It is an alpha-1 agonist and partial alpha-2 that has clinical use as a nasal decongestant. A commercially available alpha-2 agonist (brimonidine 0.33%) was the selected medication to test on 3 patients with DM in the study. All participants in the study used this topical formulation to active lesions on the face and trunk with subjective diminishing of erythema in all patients within 30 minutes. Two patients who continued usage had sustained results at week 2 and week 6 respectively.
      Discussion of incorrect answers
      • a)
        Wong et al. described the molecular characteristics of DM by skin biopsy samples (
        • Wong D.
        • Kea B.
        • Pesich R.
        • Higgs B.W.
        • Zhu W.
        • Brown P.
        • et al.
        Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases.
        ). They found 964 unique genes to DM by microarray. There were key DM signature expression genes found in the IFN signaling pathway. IFN-inducible genes were found in the skin and muscle, which relate to inflammation and complement activation and, in turn vascular and endothelial damage. Furthermore, IFN signature patterns are found in the peripheral blood of DM patients. In fact, IFN-inducible genes were nearly identical in both DM and lupus erythematosus.
      • b)
        The cutaneous vascular changes in dermatomyositis are likely tied to the underlying immunopathology. The primary target of DM autoantibodies are endothelial capillaries, which activates the complement pathway to induce swelling, perivascular inflammation, and capillary ischemia and necrosis (
        • Dalakas M.C.
        • Hohlfeld R.
        Polymyositis and dermatomyositis.
        ). This clinically manifests as the violaceous facial-truncal eruption and myositis associated with DM. Clinically evident microangiopathy can best be seen at the nailfold by capillaroscopy as tortuosities, enlarged, dilated capillaries and microhemorrhages (
        • Manfredi A.
        • Sebastiani M.
        • Cassone G.
        • Pipitone N.
        • Giuggioli D.
        • Colaci M.
        • et al.
        Nailfold capillaroscopic changes in dermatomyositis and polymyositis.
        ). In this study, the authors detected more severe changes at the nailfold in patients with shorter disease duration, and more branched capillaries signified chronic longstanding disease.
      • c)
        IFN-gamma is an important mediator of immunity and inflammation. STAT1 is a transcription factor which is activated by IFN and also activates transcription of downstream IFN-stimulated genes (
        • Ramana C.V.
        • Chatterjee-Kishore M.
        • Nguyen H.
        • Stark G.R.
        Complex roles of Stat1 in regulating gene expression.
        ). IF1H1 gene (interferon induced with helicase C domain 1) also known as MDA-5 codes for an RNA receptor that activates type I interferon signaling. Polymorphisms in IF1H1 confer increased risk of developing autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis (
        • Cen H.
        • Wang W.
        • Leng R.X.
        • Wang T.Y.
        • Pan H.F.
        • Fan Y.G.
        • et al.
        Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis.
        ).
      • d)
        Facial erythema is a key diagnostic feature of rosacea and can present as either transient flushing or persistent erythema. Patients with rosacea are also more prone to vasodilatation due to various triggers in the environment. Brimonidine 0.33% gel is a commercially available alpha-2 agonist that is approved for rosacea erythema. It is well known that brimonidine gel has selective vasoactive effects on small diameter vessels. In clinical trials, patients reported improvement in facial redness with high patient-reported satisfaction measures and clinician graded erythema. The effects can last for 12 hours. A small percentage of patients complain of worsening erythema or flushing after topical application, which resolves within 24 hours (
        • Layton A.M.
        • Schaller M.
        • Homey B.
        • Hofmann M.A.
        • Bewley A.P.
        • Lehmann P.
        • et al.
        Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study.
        ).

      Supplementary Material

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