A Wolf in Sheep s Clothing Cautionary Tales from Eczema Clinic

Transcription

1 A Wolf in Sheep s Clothing Cautionary Tales from Eczema Clinic Mark Boguniewicz, MD Professor, Division of Allergy-Immunology Department of Pediatrics National Jewish Health and University of Colorado School of Medicine

2 Disclosures Research Grants: NIH/NIAID, Anacor Consultant/Advisory Board: Celgene, Regeneron

3 Objectives At the end of this session, participants will be able to: 1. Recognize diseases that may be misdiagnosed as atopic dermatitis 2. Utilize appropriate testing in patients where the diagnosis of atopic dermatitis is in question

4 Many roads lead to eczema

5 Differential diagnosis/comorbidities Fig 1. Flow chart of the diagnosis and management of AD J Allergy Clin Immunol 2013;131:295

6 Differential diagnosis of AD Congenital disorders Netherton's syndrome Chronic dermatoses Seborrheic dermatitis Contact dermatitis (allergic or irritant) Nummular eczema Lichen simplex chronicus Infections and infestations Scabies HIV-associated dermatitis Malignancy Cutaneous T cell lymphoma (mycosis fungoides/sézary syndrome) Boguniewicz M, Leung DY. Middleton s Allergy 2014 Immunodeficiencies Wiskott-Aldrich syndrome SCID Hyper-IgE syndrome DOCK8 mutations IPEX Metabolic disorders Zinc deficiency Pyridoxine (vitamin B 6 ) and niacin deficiency Multiple carboxylase deficiency Phenylketonuria Proliferative disorder Letterer-Siwe disease

7 Worsening eczema despite improved adherence with topical steroid 34 year old female with eczematous rash since childhood presents for worsening rash. Previously responsive to mid-potency topical steroid applied BID prn. Past month, eczema has gotten progressively worse despite being adherent to a twice daily regimen of triamcinolone 0.1% ointment. She has also developed eczematous rash on her face primarily around her nose. She does use a nasal steroid (budesonide) spray for chronic rhinitis. Patient wonders if she has developed a new food allergy.

8 Exam On exam, she has erythematous papules in perinasal region and excoriated eczematous patches involving antecubitals and flexural aspects of forearms as well as distal lower extremities

9 And on further evaluation T.R.U.E. test positive to Budesonide

10 Contact Dermatitis ACD in the differential diagnosis of AD, but can also complicate AD

11 Cross-reactivity of corticosteroids When patch tests show allergy to a specific topical steroid, it is likely that the patient will also be allergic to others Budesonide (Class B) allergy may result in allergy to fluocinolone, triamcinolone, desonide and X-react with Class D2 (e.g. hydrocortisone-17-butyrate) Tixocortol-21-pivalate (Class A) allergy may result in allergy to hydrocortisone acetate, prednisolone, methylprednisolone Hydrocortisone-17-butyrate (Class D2) allergy may result in allergy to prednicarbate, hydrocortisone valerate and X-react with Class A and budesonide Other steroid classes: Class C, e.g. desoximetasone, dexamethasone Class D1, e.g. clobetasol, betamethasone,, mometasone, fluticasone Jacob SE, et al. J Am Acad Dermatol 2006;54:723-7

12 American Contact Dermatitis Society Allergen of the Year 2005: Corticosteroids

13 A pragmatic approach to patch testing atopic dermatitis patients: Clinical recommendations based on expert consensus opinion * *e.g. head/neck predominance, hand or foot, eyelid, perioral Chen JK, et al. Dermatitis 2016;27:186

14 Eczema with recurrent pneumonias 4 y/o female sent by Pulmonary service for allergy evaluation with history of recurrent pneumonias and sinusitis

15 The rest of the story Onset of recurrent pneumonias at 2 months of age Underwent lobectomies of RLL (age 2 y), then RML (age 3 y) History of extremity fracture with minor trauma Mother described patient getting uglier

16 Hyper-IgE syndrome Multisystem disorder characterized by eczema, skin abscesses, recurrent staphylococcal infections of the skin and lungs, pneumatocele formation, candidiasis, eosinophilia, and elevated serum levels of IgE Nonimmunologic features of HIES include characteristic facial appearance, scoliosis, retained primary teeth, joint hyperextensibility, bone fractures after minimal trauma, and craniosynostosis Heterozygous mutations in signal transducer and activator of transcription 3 (STAT3) transmitted as autosomal dominant trait shown to be a cause of HIES (~60-70% cases) STAT3 crucial for IL-6 mediated regulation of TH17 cells that are significant source of IL-17, a proinflammatory cytokine involved in host defense vs S. aureus and Candida Woellner C, et al. J Allergy Clin Immunol 2010;125:424

17 Features including cardinal features of HIES Woellner C, et al. J Allergy Clin Immunol 2010;125:424

18 Eberting CL, et al. Arch Dermatol 2004;140:1119 Intraepidermal eosinophilic pustule

19 Grimbacher B, et al. N Engl J Med 1999;340:692

20 Grimbacher B, et al. N Engl J Med 1999;340:692

21 Pneumatocoeles with aspergilloma in HIES Freeman AF, et al. J Allergy Clin Immunol 2007;119:1234

22 Clinical presentation of patients with and without STAT3 mutations Schimke LF, et al. J Allergy Clin Immunol 2010;126:611

23 NIH Scoring HIE 15 likely HIES 10 unlikely HIES Grimbacher B, et al. Am J Hum Genet 1999;65:735

24 Sensitivity and specificity of clinical findings in patients with HIES and STAT3 mutations Schimke LF, et al. J Allergy Clin Immunol 2010;126:611

25 Diagnostic guidelines for STAT3- mutant HIES Possible: IgE > 1000 IU/mL & weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face and high palate Probable: These characteristics & lack of TH17 cells or family history for definitive HIES Definitive: These characteristics & dominantnegative heterozygous mutation in STAT3 Woellner C, et al. J Allergy Clin Immunol 2010;125:424

26 Very verrucous eczema 7 y/o Saudi male with eczema since 8 mo age treated with topical CS by Derm Recurrent skin infections, 1 cellulitis, no deep abscesses; recurrent OM S/P PETx3; pneumonias (4/5 walking, 1 hospitalization) Recalcitrant warts FH + allergies Exam with excoriated eczematous patches on extremities and ear, verrucous lesions and several dystrophic nails on hands & feet, no pustules or vesicles

27 The rest of the story Previous serum IgE ~ 6000 IU/ml Diagnosis of Job syndrome previously raised, but no abscesses, no pneumatoceles, no retained primary teeth, no boney fractures or facial anomalies STAT-3 mutation negative Additional FH at NJH parents are 1 st cousins Additional testing DOCK8 mutation positive

28 Immunodeficiency with Dedicator of cytokinesis 8 (DOCK8) mutations DOCK8 encodes a protein implicated in the regulation of the actin cytoskeleton Susceptibility to viral infections, defective CD4+ and CD8+T-cell activation and TH17 cell differentiation, impaired eosinophil homeostasis and dysregulation of IgE, eczema Mutations in DOCK8 are responsible for many cases of AR HIE syndrome Englehardt KR, et al. J Allergy Clin Immunol 2009;124:1289

29 Cutaneous manifestations of DOCK8 deficiency syndrome Chu E, et al. Arch Dermatol 2012;148:79 2

30 Immunodeficiency with DOCK8 mutations Herpes simplex virus, Human papilloma virus, Molluscum contagiosum Zhang Q, et al. N Engl J Med 2009;361

31 Mizesko MC, et al. J Allergy Clin Immunol 2013;131:840

32 Aydin SE, et al. J Clin Immunol 2015;35:189

33 DOCK8 mutations Molluscum contagiosum, Human papilloma virus, encephalitis CNS involvement Englehardt KR, et al. J Allergy Clin Immunol 2009;124:1289

34 Vaccine strain varicella-zoster virus induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency Sabry A, et al. J Allergy Clin Immunol 2014;133:1225

35 DOCK8 mutations in 44 of 46 families Englehardt KR, et al.j Allergy Clin Immunol 2015;Feb 25

36 Infected infant You are asked to see a 3 month old male with onset of eczematous rash at ~ 1 month of age His pediatrician is concerned about open, infected lesions and about using topical steroids at this age

37 The rest of the story Chronic diarrhea and poor weight gain

38 Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genodermatosis associated with dermatitis, enteropathy, type 1 diabetes, thyroiditis, hemolytic anemia, and thrombocytopenia IPEX results from mutations of FOXP3, a gene located on the X chromosome that encodes a DNAbinding protein required for development of regulatory T cells Nieves DS, et al. Arch Dermatol 2004;140:466

39 Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome Halabi-Tawil M, et al. Br J Dermatol 2009;160:645 psoriasiform dermatitis

40 Eczema in infant 6 week old infant with fairly typical eczematous rash

41

42 The rest of the story On closer exam, you observe petechiae

43 Review of blood smear, as you suspected Microthrombocytopenia

44 Wiskott-Aldrich syndrome Eczema & petechiae & hemorrhage

45 Cutaneous manifestations in patients with WAS Ecchymosis & Petechiae (58%) Eczema (71%) Loyola Presa JG et al. Arch Dis Child 2013;98:304 Cutan Infect (17%)

46 Wiskott-Aldrich syndrome X-linked inheritance with mutations in the WAS gene (~4 :1,000,000 births) WASP encoded by WAS gene is a multifunctional signaling element expressed in immune and hematopoietic cells that plays a critical role in cytoskeletal reorganization, immune synapse formation and intracellular signaling Affected boys in classic presentation with hemorrhagic diathesis 2 to thrombocytopenia, bacterial, viral & fungal infections and eczema Albert MH, et al. Curr Opin Hematol 2011;18:42

47 WASP function in immune cells Thrasher AJ, et al. Nature Rev Immunol 2010;10

48 Intensely itchy individual 4 y/o F with 1 yr hx of itchy rash that began on buttocks (red, raised intensely pruritic papules) Dx by PCP as tinea & tx with oral antifungal Rash became more generalized including scalp Saw 3 pediatricians, 2 derms, 1 allergist - all dx eczema and tx with top CS & po ABX Subsequent tx with oral CS & antihistamine, TCI History of a single blistering lesion

49 ROS No recurrent fevers, nl growth Positive for rec GI upset, no emesis, diarrhea

50 On exam Well developed, well nourished 4 y F contantly scratching Skin with multiple excoriated erythematous papular lesions predominantly on extremities, but also trunk including R axilla, ears, scalp with normal appearing skin between lesions without lichenification or xerosis No pustules or vesicles Hair and nails nl

51 Prior studies Evaluation CBC & Biochem panel nl IgG, A, M & E - nl sige <0.35kU/L milk, egg, wheat, peanut, corn, potato NJH studies HSV culture negative PST all negative to select inhalants & foods with positive histamine control Tissue transglutaminase (ttg) IgA 247 (0-19)

52 The rest of the story Patient sent to Univ Ped Derm for skin bx with DIF - bx not done as consultant felt pt had AD with recommendation to d/c freq baths, change triamcinolone to fluocinolone and increase dose of hydroxyzine Patient saw 2 more dermatologists back home (total of 5) before bx with DIF done, consistent with dermatitis herpetiformis

53 Dermatitis herpetiformis

54 Dermatitis herpetiformis Autoimmune blistering disease with classical presentation characterized by intensely pruritic polymorphous lesions symmetrically located on extensor surfaces with concentration on the elbows, knees, scapulae, shoulders, sacrum, hairline, and scalp Papillary dermal neutrophilic microabscesses seen on routine biopsy and similar distribution of granular deposition of IgA on DIF confirms diagnosis Nearly all patients will have clinical or subclinical evidence of small bowel villous atrophy as DH is the cutaneous manifestation of gluten-sensitive enteropathy associated with HLA DQ2 & 8 Junkins-Hopkins JM. J Am Acad Dermatol 2010;63:526

55 Both conditions caused by immunologic reaction to ingested gliadin found in wheat, rye, barley and both associated with circulating IgA antibodies against endomysium and tissue transglutatminase (ttg) Patients with DH also have IgA antibodies directed against epidermal transglutaminase (etg), which is homologous to ttg A population of non cross reactive anti-etg IgA antibodies are found only in DH patients, suggesting that etg is the target in DH

56 Dermatitis herpetiformis Neutrophilic microabscesses in dermal papillae Granular IgA

57 Unusual presentations of DH Although name reflects clinical presentation of herpetiform vesicles, these are often immediately excoriated, resulting in erosions, crusted papules or areas of postinflammatory dyschromia, or pts may have erythema, urticarial plaques or papules Severe pruritus, burning and/or stinging, alone or preceding the eruption by 8 to 12 hours are often presenting symptoms simulating scabies DH usually occurs in patients between 20 and 40 years of age, but the condition is not restricted to adults Children with recalcitrant eczematous lesions, pruritic impetigo and papular urticaria may have DH

58 Dermatitis herpetiformis Scabies!

59 Puzzling pruritic patches 16-year old male with onset of itchy eczematous rash at ~ 7 years of age: initially on L ankle, progressed to trunk and extremity involvement Chest lesion has cracked and bled for approximately five years Treated with various topical steroids with partial improvement ROS: No recurrent fever, weight loss, adenopathy, abscesses, blistering lesions, alopecia or nail dystrophy

60 Physical Examination: T 36.6 C, HR 62, RR 16, BP 110/59, Hght 174 cm (50 th %-ile), weight 97.4 kg (>95 th %-ile) Not chronically ill in appearance, no LA or HSM Skin: large excoriated plaque on the left chest wall with several eczematous patches on back, gluteal folds, extensor surfaces of the lower extremities. Hair and nails normal

61 The rest of the story Skin biopsy sent showed an atypical lymphocytic infiltrate consistent with mycosis fungoides Referred to the MF Clinic at University Hospital and started on PUVA twice weekly with good response. After 6 months, repeat biopsies negative, PUVA D/C d. Patient remains in remission

62 Mycosis fungoides happens The most common form of CTCL Epidermotropic neoplasm of CD4+ T cells Robert C, Kupper TS. N Engl J Med 1999;341:1817

63 Cutaneous T cell lymphoma Mycosis fungoides - skin is variably affected by flat patches, thin plaques or tumors - is the most common form of CTCL Patch or plaque lesions have a predilection for non sunexposed areas (e.g., the buttocks, medial thighs, and breasts), although any area of the skin may be affected Insidious in onset, not uncommon to go unrecognized for # years, most often misdiagnosed as chronic contact dermatitis, atopic dermatitis, or psoriasis Lesions may become variably thickened, may coalesce to form larger plaques, or may undergo partial involution, leaving residual annular plaques Patches and plaques may show hypopigmentation or hyperpigmentation, atrophy, and petechiae

64 Cutaneous manifestations of MF Erythrodermic MF Girardi M, et al. N Engl J Med 2004;350:1978

65 Stevens SR, et al. Br J Dermatol 2003;149:513

66 Lymphocytic infiltrate in superficial dermis with individual lymphocytes among epidermal keratinocytes defines epidermotropism that characterizes this lymphoma Clustering of clonal T cells around Langerhans cells (Pautrier s microabscesses) suggests dependence of T cells on interactions with these DCs Lymphocytes may show varying degrees of atypia (pleomorphic, hyperchromatic or convoluted nuclei) In addition to routine H&E, staining of skin-biopsy specimens with a panel of lymphocyte markers helps define malignant clone for subclassification (MF positive for T-cell receptor associated with more aggressive disease than MF without receptor rearrangement)

67 MF with skin-homing T cells E-selectin CLA Girardi M, et al. N Engl J Med 2004;350:1978

68 Examination of multiple biopsy specimens from various lesions at various times will increase the likelihood that an accurate diagnosis will be made and PCR analysis of T-cell receptor genes to determine clonality may also be helpful

69 AD Program Consult Asked to see a 3 y/o male for severe eczema: onset ~ 6 mo age, severe for past 10 mo Constant scratching, sleep disturbance After failing TCS, CsA x 5 mo w/out benefit (also concern for renal SE) Oral & IM steroids give partial improvement with subsequent worsening

70 Additional history Allergy history: Food allergy to peanut (+/ tree nuts & seeds) with anaphylaxis s/p milk & egg elimination Other PMH: Wheezing with viral illness with albuterol response FH: MOC with AR, no sibs

71 Additional history Labs prior to NJH: serum IgE > 5000 IU/ml Concern for HIE syndrome Also with enlarged LNs, considering LN biopsy

72 Additional history Infection history: Superficial skin infections, no MRSA, no deep abscesses No pneumonias No HSV, MC, VV Add: No boney fx, dental abn, nail abn; previously nl hair, now sparse with freq rubbing; G&D nl Does this patient need an extensive (expensive) immune work up?

73 Additional history Patient does not tolerate baths or any topical moisturizers or meds due to c/o hurting Treatment (when possible) includes layer of petrolatum with topical steroid on top

74 After 3 days in ADP

75 Key take home message (while searching for zebras): Most pediatric patients with eczematous rashes (other than diaper dermatitis) will have atopic dermatitis Boguniewicz M, et al. J Allergy Clin Immunol 2013;132:511

76 Questions?