Contact dermatitis Presented by Planee Vatanasurkitt, MD. 20111007

1. Contact dermatitis : role of immune response in allergic contact dermatitis Planeevatanasurkitt,MD

2. 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

3. 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 etiology

4. 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 Contact dermatitis 2005;53:189-200

5. 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 ClinImmunol 2010;125:S138-49.

7. histology Spongiosis: predominant histologic feature of CD

8. Antigen presenting cell in contact dermatitis Langerhans cells keratinocytes

9. 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

10. 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

11. Cytokine in LC migration in response to hapten TNF-αand IL-1β signals are required for LC migration during the initiation phase of ACD

12. 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

13. 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

14. keratinocytes In the absence of CD80/CD86,antigen presentation in the context of MHC class II leads to clonalanergy and tolelence

15. 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+

17. Tolerance mechanism

18. lymphocyte T cells B cells NKT cells T reg cells NK cells

19. 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

20. 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 ClinImmunol 2005;1:75-86 J Immunol 2004:173:3178-3185

21. 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

22. 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

23. T cell IFN-γ classically produced by Th1 CD4+T cell IFN- γi n CHS shown to be produced by CD8+ T cells IFN- γis important in the pathogenesis of cellular infiltration associated with CHS while cutaneous edema is IFN-γ independent J Exp Med 1996;183:1001-1012

24. 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

25. 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

26. 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,theTreg 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

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

28. Clinical evaluation Diagnosis of allergic contact dermatitis from clinical presentation and possible exposure to contact allergen

29. Systemic contact dermatitis localized or generalized inflammatory skin disease in contact-sensitized individuals exposed to hapten orally, transcutaneously, intravenously, or by means of inhalation Cause Metal (cobalt, copper, chromium, gold, mercury, nickel, and zinc) Medicationscorticosteroids, 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 medicine J Allergy ClinImmunol 2010;125:S138-49.

30. 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 areas absence of systemic signs and symptoms J Allergy ClinImmunol 2010;125:S138-49.

31. 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 guidelines ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY, VOLUME 97, SEPTEMBER, 2006

32. Investigation: Patch tesing Indicated in patients with chronic,pruriticeczematous,orlichenified 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

33. 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 allergens T.R.U.E test serve as screening tool in allergist practice J Allergy ClinImmunol 2010;125:S138-49.

34. 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 ClinImmunol 2010;125:S138-49.

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

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

37. Current opinion in pediatrics 2009,21;491-498

38. Standard patch test

39. CD in thailand : patch test result

40. J Med Asso Thai vol 93 supl 7 2010

46. Allergen

47. 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

48. Determining clinical relevance

49. Investigation Repeat open application test (ROAT) Improving reliability of interpreting tests for leave-on products suspected allergens are applied to antecubitalfossa 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 ClinImmunol 2010;125:S138-49.

50. 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 J Allergy ClinImmunol 2010;125:S138-49.

51. 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) J Allergy ClinImmunol 2010;125:S138-49.

52. 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 containsallergensfoundin 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 reaction J Allergy ClinImmunol 2010;125:S138-49.

53. 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 reported J Allergy ClinImmunol 2010;125:S138-49.

54. 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 J Allergy ClinImmunol 2010;125:S138-49.

55. CAPB ( Cocoamidopropylbetaine ) 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 J Allergy ClinImmunol 2010;125:S138-49.

56. Medications Antibiotics and antiseptics Neomycin and nitrofurazone are potent sensitizers Neomycin sulfate can cross-sensitize with gentamicin, kanamycin, streptomycin, spectinomycin, tobramycin,andparomomycin J Allergy ClinImmunol 2010;125:S138-49.

57. 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 J Allergy ClinImmunol 2010;125:S138-49.

59. 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 fibroproliferativerestenosis J Allergy ClinImmunol 2010;125:S138-49.

60. 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

61. 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 J Allergy ClinImmunol 2010;125:S138-49.

62. 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 J Allergy ClinImmunol 2010;125:S138-49.