A Wolf in Sheep’s Clothing – Cautionary Tales from Eczema ... · Mizesko MC, et al. J Allergy Clin Immunol 2013;131:840. Aydin SE, ... •Chronic diarrhea and poor weight gain

Mark Boguniewicz, MDProfessor, Division of Allergy-Immunology

Department of Pediatrics National Jewish Health and University of

Colorado School of Medicine

A Wolf in Sheep’s Clothing –Cautionary Tales from Eczema Clinic

Disclosures

• Research Grants: NIH/NIAID, Anacor• Consultant/Advisory Board: Celgene,

Regeneron

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

Many roads lead to eczema…

Differential diagnosis/co-morbidities

Fig 1. Flow chart of the diagnosis and

management of AD

J Allergy Clin Immunol 2013;131:295

Differential diagnosis of ADCongenital disorders• Netherton's syndromeChronic dermatoses• Seborrheic dermatitis• Contact dermatitis (allergic

or irritant) • Nummular eczema • Lichen simplex chronicusInfections and infestations• Scabies • HIV-associated dermatitisMalignancy• Cutaneous T cell

lymphoma (mycosis fungoides/Sézary syndrome)

Immunodeficiencies • Wiskott-Aldrich syndrome• SCID • Hyper-IgE syndrome• DOCK8 mutations• IPEX Metabolic disorders • Zinc deficiency• Pyridoxine (vitamin B6)

and niacin deficiency• Multiple carboxylase

deficiency • PhenylketonuriaProliferative disorder• Letterer-Siwe disease

Boguniewicz M, Leung DY. Middleton’s Allergy 2014

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.

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

And on further evaluation…

• T.R.U.E. test positive to…

Budesonide

Contact Dermatitis

• ACD in the differential diagnosis of AD, but can also complicate AD

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

American Contact Dermatitis Society Allergen of the Year 2005: Corticosteroids

A pragmatic approach to patch testing atopic

dermatitis patients: Clinical

recommendationsbased on expert

consensus opinion

Chen JK, et al. Dermatitis 2016;27:186

*

*e.g. head/neck predominance, hand or foot,

eyelid, perioral

Eczema with recurrent pneumonias

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

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”

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

Features including cardinal features of HIES


Eberting CL, et al. Arch Dermatol 2004;140:1119

Intraepidermal eosinophilic pustule

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

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

Freeman AF, et al. J Allergy Clin Immunol 2007;119:1234

Pneumatocoeles with aspergilloma in HIES

Clinical presentation of patients with and without

STAT3mutations

Schimke LF, et al. J Allergy Clin Immunol 2010;126:611

NIH Scoring HIE

Grimbacher B, et al. Am J Hum Genet 1999;65:735

≥15 likely HIES≤ 10 unlikely HIES

Sensitivity and specificity of clinical findings in patients with HIES and

STAT3 mutations

Schimke LF, et al. J Allergy Clin Immunol 2010;126:611

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 & dominant-negative heterozygous mutation in STAT3


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

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 1st cousins• Additional testing……DOCK8 mutation positive

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

2

Cutaneous manifestations of DOCK8 deficiency syndrome

Chu E, et al. Arch Dermatol 2012;148:79

Immunodeficiency with DOCK8 mutations

Zhang Q, et al. N Engl J Med 2009;361

Herpes simplex virus,Human papilloma virus,Molluscum contagiosum

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

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

DOCK8 mutations

Englehardt KR , et al.J Allergy Clin Immunol 2009;124:1289

Molluscum contagiosum, Human papilloma virus,

encephalitis

CNSinvolvement

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

DOCK8 mutations in 44 of 46 families

Englehardt KR, et al.J Allergy Clin Immunol 2015;Feb 25

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


• Chronic diarrhea and poor weight gain

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 DNA-binding protein required for development of regulatory T cells

Nieves DS, et al. Arch Dermatol 2004;140:466

Cutaneous manifestations of immune dysregulation, polyendocrinopathy,

enteropathy, X-linked (IPEX) syndrome

Halabi-Tawil M, et al. Br J Dermatol 2009;160:645

psoriasiform dermatitis

Eczema in infant

• 6 week old infant with fairly typical eczematous rash


• On closer exam, you observe… petechiae

Review of blood smear,as you suspected…

Microthrombocytopenia

Wiskott-Aldrich syndrome

Eczema & petechiae & hemorrhage

Cutaneous manifestations in patients with WAS

Loyola Presa JG et al. Arch Dis Child 2013;98:304

Eczema (71%)

Cutan Infect (17%)

Ecchymosis & Petechiae (58%)

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

Thrasher AJ, et al. Nature Rev Immunol 2010;10

WASP function in immune cells

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

ROS

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

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

Evaluation

• Prior studies– 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)


• 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

Dermatitis herpetiformis

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 & 8Junkins-Hopkins JM. J Am Acad Dermatol 2010;63:526

• 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


Neutrophilic microabscesses in dermal papillae

Granular IgA

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


Scabies!

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

Physical Examination: T 36.6 C, HR 62, RR 16, BP 110/59, Hght 174 cm (50th %-ile), weight 97.4 kg (>95th %-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


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

Robert C, Kupper TS. N Engl J Med 1999;341:1817

Mycosis fungoides happens…•The most common form of CTCL• Epidermotropic neoplasm of CD4+ T cells

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 sun-

exposed 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

Cutaneous manifestations of MF

Girardi M, et al. N Engl J Med 2004;350:1978

Erythrodermic MF

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

• 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)

MF with skin-homing T cells

Girardi M, et al. N Engl J Med 2004;350:1978

CLA

E-selectin

• 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

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

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

Additional history

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

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 nlhair, now sparse with freq rubbing; G&D nl

Does this patient need an extensive (expensive) immune work up?

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

After 3 days in ADP…

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

Questions?

Documents

A Wolf in Sheep’s Clothing – Cautionary Tales from Eczema ... · Mizesko MC, et al. J Allergy Clin Immunol 2013;131:840. Aydin SE, ... •Chronic diarrhea and poor weight gain