Contact dermatitis

CONTACT DERMATITIS : ROLE OF IMMUNE RESPONSE IN ALLERGIC CONTACT DERMATITIS Planee vatanasurkitt,MD

OUTLINE

Immune cells in contact dermatitis Classification of contact dermatitis Investigation in contact dermatitis Data of patch testing in contact dermatitis

Thailand study Common allergen in contact dermatitis treatment

INTRODUCTION

Contact dermatitis CD is one of the most common inflammatory skin disease

CD represents majotity 79-90% annually of skin related occupational complaints

CD can be divide into four cattegories base on etiologyIrritant contact

dermatitis non immunological

Photocontact dermatitis Chemical require light –induced in UV spectrum to cause skin response

Contact urticaria IgE mediated

Allergic contact dermatitis

Complex Immune mechanism : induction and elicitation

PATHOPHYSIOLOGY

In1935 studies of 2,4-dinitrochlorpbenzene DNCB sensitization guinea –pigs

Electrophilic component of hapten and nucleophilic side chain of target protein in skin

Chemical that are not normally electrophilic can converted to properties of hapten by air oxidation or cutaneous metabolism

Electrophilic component

nucleophilic

Aldehydes, ketone,amide metal ion

Lysine,cyctein ,histidine

Contact dermatitis 2005;53:189-200

ACD 20% prototype of type IV cell-mediated

hypersensitivity reaction ICD 80%

nonimmunologic, multifactorial, direct tissue reaction

T cells activated by nonimmune, irritant, or innate mechanisms release proinflammatory cytokines

dose-dependent inflammation ACD and ICD frequently overlap because

many allergens at high enough concentrations can also act as irritants

PATHOPHYSIOLOGY

J Allergy Clin Immunol 2010;125:S138-49.

HISTOLOGY

Spongiosis: predominant histologic feature of CD

ANTIGEN PRESENTING CELL IN CONTACT DERMATITIS

Langerhans cells keratinocytes

LANGERHANS CELLS

At steady state 90% LC exhibited relatively little mobility

After application hapten dendrite surveillance extension and retraction cycling habitude [dSEARCH] and lateral migration of LC

The amplification of dSEARCH is mediated by IL-1α and TNF-α ,cytokine produced by keratinocytes

LANGERHANS CELL

LC exhibit increase expression of CD 83 ,marker for LC maturation ICAM-1,adhesion molecule CD 40,B7-1[CD80] B7-2 [CD86], co-

stimulation molecule Expression of these marker is specific to

hapten-exposed LC, dermal irritants trigger LC migration but not result in LC surface marker changes

CYTOKINE IN LC MIGRATION IN RESPONSE TO HAPTEN

TNF-α Via TNFR2

IL-1 family IL-1α, IL-1β ,IL18 IL1β rapidly produced by LC and act through IL1RI to produce TNF-α

TNF-α and IL-1β signals are required for LC migration during the initiation phase of ACD

LANGERHAN CELL

Immature LC express CCR5 and CCR6 In response to hapten exposure LC

upregulate CCR7 CCR7-CCL 19,21 targeting LC to lymph node CCL19 CCL21 express in lymph node

paracortex CCL21 expressed by afferent lymphatic

endothelial cell

KERATINOCYTES

KC are the source of cutaneous TNF-α expression after hapten exposure

Express IL-1 receptors which response to LC –derived IL 1 β,leading to expression of TNF-α

KC also express ICAM-1 in the presence of IFN-γ

T cell ,source of IFN-γ, express CD11a which bind to ICAM-1 on keratinocyte

KERATINOCYTES

In the absence of CD80/CD86,antigen presentation in the context of MHC class II leads to clonal anergy and tolelence

KERATINOCYTES

KC can express IL 10 particularly in response to hapten exposure

KC express IL-16,only first appears 6 h after hapten exposure with maximal expression at 24 h after exposure during elicitation

KC express high level of RANKL [receptor activator of NF-κB ligand ] this molecule interacts with its receptor RANK on Langerhans cells leading to upregulation cell surface marker including CD205 and CD86,CD205 associated with induction of CD4+ CD25+

TOLERANCE MECHANISM

LYMPHOCYTE

T cells B cells NKT cells T reg cells NK cells

T CELL

Primary effector cell of ACD are CD8+ cell Trinitrophenyl TNP is strong hapten that

induced predominantly CD8+ T cell CHS response and can triggered normal CHS response in CD8+ T cell depleted mice

In the absence of CD8+ T cell, CD4+T cells are capable of mediating the CHS to trinitrophenyl

J Interferon Cytokine Res 2002;22:407-12

T CELL

Invitro studies indicated that hapten-specific CD8+ T cell induce Fas-mediated apoptosis of CD 4+ T cells

During sensitization CD8+T cell trigger apoptosis of CD4+ T cell, there by eliminating hapten-specific CD4+ T cell priming/expansion and ensuring CD8+ T cell are dominant effector cell

Expert Rev Clin Immunol 2005;1:75-86J Immunol 2004:173:3178-3185

T CELL

Cytokines involved in T helper cell type 1 proliferation/activation are consider important during development of CHS responses

Contact allergen triggered KC produce IL12 leading to proliferation of T cell into Th1 phenotype

Scand J immunol 2004 ;59:385-394

T CELL

In vitro studies demonstrated that both initiation and elicitation phases of DNFB-mediated ACD were significantly blocked by IL-12 neutralizing antibodies

Conclusion IL-12 is important in the pathogenesis of ACD

J Immunol 1996;156:1799-1803

T CELL

IFN-γ classically produced by Th1 CD4+T cell IFN- γi n CHS shown to be produced by CD8+

T cells

IFN- γ is important in the pathogenesis of cellular infiltration associated with CHS while cutaneous edema is IFN-γ independent

J Exp Med 1996;183:1001-1012

B CELL

Initial hapten exposure B-1 proliferate and produce IgM while B-2 cell remain at pre-exposure levels

IgM antibody activates complement

C5a trigger inflamation through binding to C5a receptor on mast cell and platelet leading to recruitment of effector T cells

J Exp Med 2002;196:1277-1290

Trends Immunol 2004;25:441-449

NKT CELLS

Characterizes by expression CD 161 and α /β chains of T cell receptor

TCR on invariant NKT cell bind highly conserved glycolipids in the context of CD1d

The production of IL-4 by iNKT cells shown to be toll-like receptor dependent

TREG CELLS

Express CD25, cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] ,and forkhead box P3 [Foxp3]

In individuals who do not develop ACD to nickel,the Treg cells were able to inhibit effector T cells activation while individuals who exhibit ACD to nickel were unable to suppress nickel-specific effector T cell activation in vitro

Treg are involved in ACD suppression and hapten tolerance

NK CELLS

NK cell have ability to acquire hapten specific memory and mediated CHS

CLINICAL EVALUATION

Diagnosis of allergic contact dermatitis from clinical presentation and possible exposure to contact allergen

SYSTEMIC CONTACT DERMATITIS localized or generalized inflammatory skin

disease in contact-sensitized individuals exposed to hapten orally, transcutaneously, intravenously, or by means of inhalation

CauseMetal (cobalt, copper, chromium, gold, mercury, nickel, and zinc)

Medications corticosteroids, antihistamines (diphenhydramine, ethylenediamine, hydroxyzine, and doxepin), miconazole, terbinafine, neomycin,gentamicin, erythromycin, pseudoephedrine, benzocaine, tetracaine, oxycodone, IVIG, aminopenicillins, 5-aminosalicylic acid, naproxen, allopurinol, mitomycin C, 5-FU

Herbal medicineJ Allergy Clin Immunol 2010;125:S138-49.

DRUG INDUCED SCD

Symmetric drug-related intertriginous and flexural exanthema

Criteria for diagnosis :exposure to systemic drug at first or

repeated dosing (contact allergens excluded)

erythema of gluteal/perianal area, V-shaped erythema of inguinal/perianal area, or both

involvement of at least 1 other intertriginous/flexural localization

symmetry of affected areasabsence of systemic signs and symptoms


OCCUPATIONAL CONTACT DERMATITIS 4 of 7 criteria must be positive to conclude OCD

clinical appearance is consistent with CD cutaneous irritants or allergens are present in

workplace anatomic distribution of dermatitis is consistent with

skin exposure to chemicals in course of various job tasks

temporal relationship between exposure and onset of symptoms is consistent with CD

nonoccupational exposures are excluded as probable causes of dermatitis

dermatitis improves away from work exposure and reexposure causes exacerbation

there are positive-reaction and relevant patch tests performed according to established guidelinesANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY, VOLUME 97, SEPTEMBER, 2006

INVESTIGATION: PATCH TESING

Indicated in patients with chronic,pruritic eczematous,or lichenified dermatitis in whom ACD is suspected

Affected by oral corticosteroid [>20 mg of prednisolone /day or equivalent] cancer chemotherapy,immunosuppressive drug

Topical corticosteroid should be discontinued for 5-7 days before patch testing

INVESTIGATION

Sources of allergens T.R.U.E. TEST :not US FDA approved But recommended by CD experts

Numbers of allergens ideal number remains controversial T.R.U.E. Test contains 29 allergens

higher false-negative reactions to neomycin, thiuram mix, balsam of Peru, fragrance mix, cobalt, and lanolin

NACDG series range from 65 to 70 allergensT.R.U.E test serve as screening tool in

allergist practice


PATCH TEST TECHNIQUE

applied to upper or middle back areas (2.5 cm lateral to midspinal reference point) free of dermatitis and hair

kept in place for 48 hours read 30 minutes after removal of patches second reading should be done 3 to 5 days

after initial application Metals , topical antibiotics , topical

orticosteroids, and PPD can elicit positive reactions after 7 days

Nonstandardized patch tests tested at 1:10 to 1:100 dilutions J Allergy Clin Immunol 2010;125:S138-49.

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY, VOLUME 97, SEPTEMBER, 2006

DIAGNOSIS

Clinical presentation of rash with history of exposure agent confirmed with possible patch test result

Current opinion in pediatrics 2009,21;491-498

STANDARD PATCH TEST

CD IN THAILAND : PATCH TEST RESULT

Chulalongkorn U. Siriraj Thammasat U

129 patient 323 patient 157 patient

34 standard patch test

European standard International patch test series

23 Europeanstandard

June 2003-2004 Jan 2004-Dec2006 June 2008-2009

Positive patch test 72.13 %nickel sulfate 18.6%Cobalt chloride 17%P-phynylenediamine 1.55%Fragrance mix 14.73 %

Positive patch test nickel sulfate 26.6%Cobalt chloride 16.4%P-phynylenediamine 10.3%Fragrance mix 20.7%

Positive patch test 44.6%nickel sulfate 26.8%Cobalt chloride 7.6%P-phynylenediamine 7%Fragrance mix 7%

J Med Asso Thai vol 93 supl 7 2010

area agent

Face and eyelid Only eyelid :Gold ,fragrances, preservative,nickel,thiuram,cocamidopropyl betain,amidoamine[shampoo] tosylamide formaldehyde resin[nail polish]Mixed facial and eyelid dermatitis: nickel,kathon,fragrance

hand Patch test in hand eczema :Rubber element,nickel sulfate,potassium dichromateEntire hands :thiuram mix PPD, chromate balsam of peruFinger and digital spaces: nickel, cobalt

feet Most common positive patch test with ACD exclusive on feet : rubber compound

ALLERGEN

nickel jewelry

neomycin Topical antibiotic

Balsam of Peru fragrance

Thimerosal Otic opthalmic ,antiseptic

Chromate Leather products

Thiuram Rubber accelerants

Lanolin emollients

Formaldehyde preservative

Paraphenylenediamine Permanent hair dye, Henna

COMMON COMBINATION

PPD and benzocaine Thiuram mix carba mix mercapto mix Quaternium 15 and paraben Cobalt and nickel Patients older than 40 years are prone to

multiple sensitivities Repeat open application test might confirm

the presence or absence of ACD

DETERMINING CLINICAL RELEVANCE

definite Suspected item positive

probable Antigen could present in skin contact and clinical consistant

possible Skin contact with materials contain allergen was likely

INVESTIGATION Repeat open application test (ROAT)

Improving reliability of interpreting tests for leave-on products

suspected allergens are applied to antecubital fossa twice daily for 7 days and observed for dermatitis

absence of reaction makes CD unlikely

If eyelid dermatitis is considered, ROAT can be performed on back of ear J Allergy Clin Immunol 2010;125:S138-49.

SELECTED CONTACT ALLERGENS

Metals Nickel

NACDG reported 18.7% of patients evaluated for ACD had positive patch test reaction to nickel

Female sensitization to nickel higher because of increased ear piercing

1% of nickel allergy have systemic reactions to nickel content of normal diet

Foods with higher nickel content include soybean, fig, cocoa, lentil, cashew, nuts, and raspberry


Gold NACDG reported that 389/4101(9.5%) had

positive patch test reactions to gold hands (29.6%); face, with seborrheic

distribution (19.3%); and eyelids (7.5%) mostly used for fashion appeal, anti-

inflammatory medication, used in electroplating industry, part of dental appliances (present with oral symptoms)


COSMETICS Common allergens in these products include

fragrances, preservatives, excipients, glues, and sun blocks

Fragrance most common cause of ACD from cosmetics results in positive patch test reactions in 10.4% of

patients ‘‘unscented’’ and ‘‘Fragrance-free’’ Fragrance mix I contains allergens found in 15% to

100% of cosmetic products and might detect ~85% of subjects with fragrance allergy

positive patch test reaction to fragrance must correlate with distribution of dermatitis and evaluation of clinical relevance, eg. positive ROAT reactionJ Allergy Clin Immunol 2010;125:S138-49.

Preservatives and excipients Lanolin : common component of consumer products It is weak sensitizer on normal skin but a stronger

sensitizer on damaged skin stasis dermatitis, are at higher risk of lanolin

sensitivity Cosmetic preservatives

Formaldehyde releasers non–formaldehyde releasers : Paraben most commonly

used preservative in cosmetics, as well as in pharmaceutical and industrial products

Type I immediate hypersensitivity reactions (contact urticaria) and SCD from ingestion of paraben-containing medications or foods have been reportedJ Allergy Clin Immunol 2010;125:S138-49.

Hair products Second most common cause of cosmetic allergy PPD (Paraphenylenediamine) is most common

cause of CD in hairdressers In hair dye users the dermatitis often spares the

scalp and usually involves the face near the hairline, eyelids, and neck

PPD cross-reacts with COX-2 inhibitor (celecoxib), sunscreens, and antioxidants used in manufacture of rubber products

New hair dyes that contain FD&C and D&C dyes have very low levels of cross-reactivity with PPD


CAPB ( Cocoamidopropyl betaine ) amphoteric surfactant often found in shampoos,

bath products, and eye and facial cleaners CAPB allergy typically presents as eyelid, facial,

scalp, and/or neck dermatitis Glycerol thioglycolate

active ingredient in permanent wave solution Unlike PPD, thioglycolates might remain

allergenic in hair long after it has been rinsed out

skin eruptions can continue for weeks after application of permanent wave solution


MEDICATIONS

Antibiotics and antiseptics Neomycin and nitrofurazone are potent

sensitizers Neomycin sulfate can cross-sensitize with

gentamicin, kanamycin, streptomycin, spectinomycin, tobramycin,and paromomycin


MEDICATIONS

corticosteroid 0.2-6% Patients with worsening of previous dermatitis or

initial improvement followed by deterioration of dermatitis after application of corticosteroids should be evaluated

Patch test should inclulde groups of simultaneously or cross reacting corticosteroid,vehicle and preservative

Cross-reactivity between groups A and D2 and groups B and D2 also has been reported

optimal patch test concentration not worked out for most corticosteroids, include pateint’s own product

30% of ACD to corticosteroids be missed if delayed 7-day reading not done


CD DUE TO SURGICAL IMPLANT DEVICES use of nickel in biomedical devices,led to

increasing concern about safety in suspected nickel-sensitized patients

Presently,high variability of care no large, evidence-based guidelines 10 patients with positive patch test reaction

to metal had in-stent restenosis associated with clinical symptoms

allergy to metals,plays relevant role in inflammatory fibroproliferative restenosis


CD DUE TO SURGICAL IMPLANT DEVICES criteria for diagnosis of cutaneous implant–

induced reaction dermatitis (localized or generalized) appearing

after implant surgery persistent dermatitis that is resistant to

appropriate therapies positive patch test result proven history to

metallic component of implant or to commonly used acrylic glues

resolution of dermatitis after removal of implant

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY, VOLUME 97, SEPTEMBER, 2006

TREATMENT

Allergen identification to improve contact avoidance

Alternatives and substitutes to cosmetics should be offered to patient to increase compliance

supportive care and relief of pruritus, cold compresses with water or saline, Burrow solution , calamine, and colloidal oatmeal baths might help acute oozing lesions

Excessive hand washing should be discouraged in hand dermatitis, and nonirritating or sensitizing moisturizers must be used after washing


TREATMENT

TC is first-line treatment for ACD For extensive(>20% BSA) and severe CD,

systemic corticosteroids might offer faster relief (12-24hr)

recommended dose is 0.5 to 1 mg/kg daily for 5 to 7 days, and only if patient is comfortable at that time is dose reduced by 50% for next 5 to 7 days


Contact dermatitis

Health & Medicine

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