Contact Dermatitis and Patch Testing: An Update for the Allergist

AAAAI 2802 Hands-On Workshop Saturday, February 23, 2013: 04:45 PM - 06:00 PM Contact Dermatitis and Patch Testing: An Update for the Allergist Luz Fonacier MD, FACAAI, FAAAAI Section Head of Allergy Program Director, Allergy and Immunology Winthrop University Hospital Professor of Clinical Medicine SUNY at Stony Brook

Disclosure Research and Educational Grants AAAAI ArTrust Genentech Dyax Baxter Speaker s Bureau Baxter

AAAAI Objectives 1. Discuss the clinical correlation of the patch test results 2. Develop a current understanding of allergic contact dermatitis and patch testing to cosmetics, medical devices and other allergens 3. Demonstrate the technique of application and interpretation of non standardized allergens as in personal products

Patterns of Cosmetic Contact Allergy Facial cosmetic dermatitis Bilateral Patchy Eyelid Neck Lips run-off pattern Cosmetics applied to face, scalp or hair often initially affect the neck Most affected site of ACD from nail varnish is the neck Consort/Connubial Dermatitis: primarily fragrance

The Science of Cosmetics Typical contact allergens tend to be clustered in a few important classes Fragrances Preservatives Excipients Glues Sun blocks

Fragrance Contact Allergen of 2007 Most common cause of ACD from cosmetic > 2800 fragrance ingredients used routinely in cosmetics ~100 are known allergens ~10-25% of PT are positive to fragrance chemicals 1.7-4% of general population predominantly women Johansen JD. Fragrance contact allergy: a clinical review. Am J Clin Dermatol 2003;4:789-98 Pratt MD et a;. North American Contact Dermatitis Group Patch-test Results 2001-2002 study period. Dermatitis 2004;15:176-83 *Buckley DA et al. The frequency of fragrance allergy in a patch-test population over a 17 year period. Br J Dermatol 2000;142:203-4 Contact Dermatitis 2003 Dec;49(6):287-9

Fragrance Fragrance Mix I Balsam of Peru Myroxylon pereirae Fragrance Mix II Cinnamic alcohol 1% Cinnamic acid Coumarin 2.5% Cinnamic aldehyde 1% Benzoyl Cinnamate Hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) 2.5% a-amyl cinnamaldehyde (amyl cinnamal) 1% Benzoyl Benzoate Citronellol 0.5% Hydroxycitronellal 1% Benzoic acid Farnesol 2.5% Geraniol 1% Vanillin Citral 1.0% Isoeugenol 1% Nerodilol a Hexyl cinnamic aldehyde 5.0% Eugenol 1% Oak moss 1% Other fragrance sensitizers: Lyral, jasmine, lavender, sandalwood, tea tree oil, ylang ylang oil, lemongrass oil, jasmine, Narcissus

Fragrance Contact Allergen of 2007 Standard fragrance mix: Fragrance mix I & Balsam of Peru pick up 60-70% of all ACD to fragrances at best (-) PT to FM I ~ 35% had (+) PT to FM II (+) PT to FM II ~1/3 had (+) PT to FM I Buckley DA et al. The frequency of fragrance allergy in a patch-test population over a 17 year period. Br J Dermatol 2000;142:203-4 Albert MR et al. Concomitant positive reactions to allergens in the patch testing standard series from 1988-1997. Am J Contact Dermat 1999. 10:219-223 Devos SA et al. Relevance of Positive Patch-Test Reactions to Fragrance Mix. Dermatitis, Vol 19, No 1 January/February), 2008: 43 47

Fragrance Mix Patch Test Low specificity Mild Irritant potential, caution with weak positive reactions Increased probability of a relevant FM patch-test Increased strength of test reaction Repeated (+) reaction on retest (+) to one of its ingredients Devos SA et al. Relevance of Positive Patch-Test Reactions to Fragrance Mix. Dermatitis, Vol 19, No 1, 2008: 43 47

Tricky Aspects of Fragrance Allergy New fragrance chemicals are constantly introduced Regulation of fragrance ingredients in cosmetics exempts fragrance formulas as trade secrets Some manufacturers do not consider essential oils to be fragrance Tree tea oil (Melaleuca alternifolia) Ylang-ylang oil (Cananga odorata) Jasmine flower oil (Jasminum officinale) Peppermint oil (Mentha piperita) Lavander oil (Lavandula angustifolia) Citrus oil (limonene) Covert fragrances - used for other than for aroma (ie preservatives) can be added to fragrance free products Bensaldehyde Benzyl alcohol Bisabolol Citrus oil Unspecified essential oils Castanedo-Tardan M & Zug K. Patterns of Cosmetic Contact Allergy. Dermatol Clin 2009 27: 265-280

Food-related contact dermatitis Myroxilon pereirae, Fragrance Mix, Cinnamic Aldehyde Myroxilon pereirae (Balsam of Peru) (2 nd ) Fragrance mix (4th) Cinnamic aldehyde (6th) Relatively specific (not very sensitive) marker for spice allergy Flavoring in gums, mouthwashes, toothpaste Sensitization to BOP in topical products may cause systemic CD from foods with BOP Warshaw E M et al. Contact Dermatitis Associated with Food: Retrospective Cross-Sectional Analysis of North American Contact Dermatitis Group Data, 2001 2004 Bauer A, Geier J, Elsner P. Type IV allergy in the processing industry: sensitization profiles in bakers, cooks and butchers. Contact Dermatitis 2002;46:228 35.

Fragrance Systemic Contact Dermatitis Foods to Avoid in Balsam-Restricted Diet Citrus fruits: oranges, lemons, grapefruit, tangerines Flavoring agents: pastries, bakery goods, candy, gum Spices: cinnamon, cloves, vanilla, curry, allspice, anise, ginger Spicy condiments: ketchup, chili sauce, barbecue sauce, chutney, Perfumed or flavored tea & tobacco Chocolate Certain cough medicines & lozenges Ice cream Cola, spiced soft drinks such as Dr Pepper Tomatoes & tomato-containing products Possible cross reactivity with Compositae ( natural & organic ) containing sesquiterpene lactones (chamomile, echinacea) ~ half of patients with (+) PT to MP who followed a low BOP diet had significant improvement of their dermatitis Salam TN, Fowler JF Jr. Balsam-related systemic contact dermatitis J Am Acad Dermatol. 2001 Sep;45(3):377-81 Paulsen E. Contact sensitization from Compositae-containing herbal remedies and cosmetics. Contact Derm 2002;47:189 198. Paulsen E, Andersen KE. Colophonium and Compositae mix as markers of fragrance allergy: cross-reactivity between fragrance terpenes, colophonium and compositae plant extracts. Contact Derm 2005;53:285 291.

Summary for Fragrance Allergy Wash on/wash off products:? Relevance of brief exposure Concentration of fragrance left on fabric is below threshold induction levels Testing to FM I & BOP picks up 60-70% of fragrance allergy* Many FM I PT reactions are weak, perhaps irritant & hard to reproduce Advising patients to avoid all fragranced products on the basis of a very weak (+) PT (? irritant) may deprive them of one of life's pleasures Storrs F J. Fragrance. Dermatitis Volume 18, Issue 01, March 2007, Pages 3-7 *Larsen W et al. Fragrance contact dermatiis: a worldwide multicenter investigation (part III)> Contact Dermatitis 2002;46:141-4

Preservatives 945 PT patients at Mayo 68.4% had at least 1 (+) reaction 47.3% had at least 2 (+) reactions 49.4% reacted to at least 1 preservative 31.2% reacted to at least 1 fragrance/botanical additive Older individuals were 3.7x more likely to have (+) PT to common preservatives than children J Am Acad Dermatolol. 2010 Nov; 63(5)789-98

Cosmetic Preservatives Formaldehyde (+) PT Non Formaldehyde (+) PT Formaldehyde* 8.4 % Methyldibromoglutaronitrile (Euxyl K 400) 5.8 % Quarternium 15* 9.3% MCI/MI 2.3 % Diazolidinyl urea* (Germall II) 3.2 % Parabens* 0.5 % Imidazolidinyl urea* (Germall) 3.0 % Chloroxylenol 0.8 % Bromonitropropane (Bronopol) 3.3 % Iodopropynylbutylcarbamate 0.4% DMDM Hydantoin (Glydant) 2.6 % Paraben, quarternium-15 & formaldehyde preservatives are frequently combined & cosensitize *** *Antigen present in the T.R.U.E. Test ** % Prevalence PT reaction based on NACDG or TT ***Albert MR et al. Concomitant positive reactions to allergens in the patch testing standard from 1988-1997. Am J Contact Dermat 1999. 10:219-223

Formaldehyde Most common potential source of exposure Cosmetics Rarely on ingredient label, direct use forbidden in some countries Contain formaldehyde releasers Permanent press textiles Increase strength, prevent shrinking, resist wrinkling (permanent press) of cellulose and rayon fibers Agner et al.formaldehyde allergy: a follow up study. Am J Contact Dermatitis 1999;10:12-17

Formaldehyde Resins Dermatitis pattern in areas where clothing fit tightly posterior neck upper back lateral thorax anterior & posterior axillary folds (spares axillary vault) waistband (spares undergarment areas) flexor Importance of pressure, friction, heat, perspiration

Formaldehyde in Textile Resin Subacute and chronic dermatitis Formaldehyde testing alone identifies only ~70% of formaldehyde resin allergic patients PT with resins as well Slow resolution of dermatitis even with careful avoidance As much as 50% still had constant dermatitis * Occasional exposure to Dress clothes on weekends is enough to maintain dermatitis *Hatch KL, Maibach HI. Textile chemical finish dermatitis. Contact Dermatitis 1986;14:1 13. Allergic Contact Dermatitis from Formaldehyde Textile Resins Fowler JF Jr, Skinner SM, Belsito DV. Allergic contact dermatitisfrom formaldehyde resins in permanent press clothing: an underdiagnosed cause of generalized dermatitis. J Am Acad Dermatol.1992;27:962 8. Reich H &Warshaw E. Allergic Contact Dermatitis from Formaldehyde Textile Resins. Dermatitis, Vol 21, No 2, 2010: pp 65 76

Treatment for Formaldehyde Resin Allergic Contact Dermatitis Use 100% silk, polyester, acrylic, nylon Linen & denim if soft & wrinkle easily Avoid easy care, permanent press, or wrinkle free Some experts also recommend avoidance of formaldehyde-releasing preservatives in personal products* AVOID FORMALDEHYDE RESINS AT ALL TIMES. Even exposure once a month is enough to cause a rash to continue Reich H & Warshaw E. Allergic Contact Dermatitis from Formaldehyde Textile Resins. Dermatitis. 2010. 21;2:65 76 *Scheman A, Jacob S, Zirwas M, et al. Contact allergy: alternatives for the 2007 North American Contact Dermatitis Group (NACDG) standard screening tray. Dis Mon 2008;54:7 156.

Food-related Contact Dermatitis Formaldehyde Allergy & Aspartame SCD in formaldehyde-sensitive patients after ingesting aspartame (artificial sweetener) in food, medicaments, vitamins Monteleukast chewable tablets (contain aspartame) granule does not Aspartame metabolized to phenylalanine, aspartic acid, & aspartic acid methyl ester methanol transported to liver Liver: methanol oxidized formaldehyde Matiz and Jacob: Systemic Contact Dermatitis Pediatric Dermatology Vol. 28 No. 4 July August 20 Jacob SE, Stechschulte S. Formaldehyde, aspartame, and migraines: a possible connection. Dermatitis 2008;19:E10 E11.11

Quarternium 15 Most common cosmetic preservative allergen Most sensitization is caused by formaldehyde releaser Most Q 15 allergic patients are also allergic to formaldehyde Castanedo-Tardan M & Zug K. Patterns of Cosmetic Contact Allergy. Dermatol Clin 2009 27: 265-280

Paraben Most commonly used cosmetic ingredient next to water (87-93%) Average total paraben exposure per person in the US is ~ 76 mg/day Cosmetics & personal products: 50 mg per day Foods: paraben is usually less than 1% Weak sensitizers in cosmetics Paraben-sensitive individuals often tolerate parabencontaining cosmetics on normal intact skin but not damaged skin Paraben paradox : only sites of healed dermatitis flare when sensitizer is applied Allison CL, Warshaw EM. Parabens: A Review of Epidemiology, Structure, Allergenicity, and Hormonal Properties. Dermatitis 2005; 16:57-66 Castanedo-Tardan M & Zug K. Patterns of Cosmetic Contact Allergy. Dermatol Clin 2009 27: 265-280

Cosmetic vehicles, emulsifiers & additives Lanolin (Wool wax alcohols) Most common sources: moisturizer, creams, cosmetics & topical medications Male sex, atopic dermatitis, & co-reactivity to other allergens were higher in lanolin-positive patients Complex mixture therefore test actual lanolin used Lanolin Paradox: sensitivity low in normal skin moderate in atopic high in stasis eczema & ulcers Erin M. Warshaw et al. Positive Patch Test Reactions to Lanolin: Cross-Sectional Data from the North American Contact Dermatitis Group, 1994 to 2006. Dermatitis. April 2009. 20;2:79-88

PROPYLENE GLYCOL Most common patterns of dermatitis in PG (single reactors) Dermatitis on the face Scattered or generalized dermatitis Uses solvent, vehicle, emulsifier or humectant thickening agent in many foods (concentration may be too low to cause skin reactions) Most common source of allergy Personal care products Topical medicaments, especially topical CS

Food-related irritant and allergic contact dermatitis Specific Allergens: Propylene Glycol Used in food colorings, foods thickening agent in cake mixes, salad dressings, soft drinks, popcorn Concentration in foods is likely too low to cause a reaction but there are reports of flares from ingestion of foods containing propylene glycol by sensitized patients flares following oral provocation (15 ml of propylene glycol) Warshaw E M et al. Contact Dermatitis Associated with Food: Retrospective Cross-Sectional Analysis of North American Contact Dermatitis Group Data, 2001 2004 Bauer A, Geier J, Elsner P. Type IV allergy in the processing industry: sensitization profiles in bakers, cooks and butchers. Contact Dermatitis 2002;46:228 35.

P-phenylenediamine (PPD) Contact Allergen of 2006 Permanent Hair Dye Theoretically, does not cause reaction if fully oxidized In reality, it is likely that PPD is never completely oxidized

New Route of Exposure Body painting & temporary tattooing (until stratum corneum is shed) Clinical course (1) acute intense eczematous response within 1-2 days of tattooing (2) subacute response: lichenoid eruptions within 1-2 week Most likely causative agent is PPD PPD sensitization is likely lifelong; may react to first attempts at hair coloring Leo V. p-phenylenediamine Dermatitis Volume 17, Issue 02, June 2006, Pages 53-55 Hesse et al. Contact Dermatitis to hair dyes in a Danish Adult population: an interview based study. Br J of Dermatol 2005; 153:132-5 Dickel H et al. Comparison of patch test with standard series among white and black racial groups. Am J Contact Dermat 2001;12:77-82

Prevention Home test appear to be predictive and could provide secondary prevention if properly used New hair dyes (semipermanent) contain FD & C and D & C dyes that appear to have very low cross reactivity with PPD Elumen Hair Color (Goldwell cosmetics Linthicum Heights, MD) Clairol Basic Instincts-Loving Care (The Proctor & Gamble Company, Cincinnati, OH) Krasteva et al. Contact Sensitivity to hair dye can be detected by the consumer open test. Eur J Dermatol 2002;12:322-6 Fautz R et al. Hair dye sensitized hairdressers: the cross reaction pattern with new generation hair dyes. Contact Dermatitis 1999;46:319-24

Cocoamidopropyl betaine Contract Allergen of 2004 Second most common allergen in shampoo Less irritating than older surfactants (sodium lauryl sulfate) but more sensitizing Positive PT are often clinically relevant Areas of Involvement Face: 30.2% Neck: 14.3% Hands: 12.7% Eyelids: 9.5% Scalp: 4.8% Scattered: 23.8% Fowler JF. Cocamidopropyl Betaine. Dermatitis 2004;15:3-4

Shampoos Typically composed of 10-30 ingredients Only 5 products in the Walgreens database were truly fragrance free Of 9 with no fragrance, 4 had fragrance related ingredients, 3 had botanical ingredients, 1 had benzyl alcohol) Matthew Zirwas and Jessica Moe Shampoos. Dermatitis, Vol 20, No 2 (March/April), 2009: pp 106 110

Emergent and Unusual Allergens in Cosmetics ACD from cosmetics is a common problem, the formulation of cosmetic products is constantly changing Shellac (lacca or gomme-laque): found in pump or aerosol hair sprays, shampoos, eyeliners, mascaras, nail lacquers, lipsticks Lipsticks Various D&C dyes & inorganic pigments in D&C yellow 11 and D&C red 7 Oily base: Castor oil (ricinus oil): suspends pigment Additives (ie. emollients), antioxidants (ie gallates), sunscreens Old allergens learn new tricks while new allergens emerge to challenge our quest for a definitive diagnosis Pascoe D et al. Emergent and Unusual Allergens in Cosmetics Dermatitis Vol 21 No 3 2010 127-137

Issues with Contact Dermatitis History not always accurate Physician s guess is almost always wrong Changing landscape of cosmetics NEW Products (New fragrance chemicals constantly introduced ) New bottles of old products New and improved products Natural products can cause allergies Poor Regulation of cosmetics industry fragrance formulas are trade secrets Some manufacturers do not consider essential oils to be fragrance (Tree tea oil, Ylang-ylang oil, Jasmine, Peppermint, Lavender, Citrus oil) Covert fragrances - used for other than for aroma (i.e. preservatives) Labels difficult to read or Incomplete Cross-reactivity and Co-reactivity Test for personal products especially for facial, eyelid and lip dermatitis Clinical Campus of Stony Brook University School of Medicine

Nickel in Biomedical Devices Reports of dermatitis to biomedical devices lead to: Consults regarding safety of medical devices in nickel-sensitized patients High variability of care in terms of testing & recommendations differences within and between countries Increased health care costs Medicolegal concerns contribute to testing Selection of more expensive & less durable option As nickel allergy incidence increases, this problem will also increase Kornik R and Zug K. Dermatitis2008;19(1):3-8 Clinical Campus of Stony Brook University School of Medicine

Pathophysiology of Metal Allergy and Implant Failure Metal Corrosion Metal tissue Deposition Necrosis Tissue Reactions Phagocytosis Foreign body giant cells Immunologic Level Endothelial cell exposure induce intercellular adhesion molecule1 expression Cutaneous reactions above implant are primarily T cell-mediated type IV rxns Tissues adjacent to implant in metal sensitive patients have elevated immune cells/markers (CD3þ T lymph, CD4þ cells, CD11cþ macrophages/dendritic cells & cells with abundant MHC class II) Watari F et al. J. R. Soc. Interface 2009;6:S371-S388 Cunningham et al. The effect of spinal instrumentation particulate wear debris : an in vivo rabbit model and applied clinical study of retrieved instrumentation cases. The Spinal Journal. 2003; 3:1. 19 32 Basko-Plluska, J et al. Cutaneous and Systemic Hypersensitivity Reactions to Metallic Implants. Dermatitis, 2011. 22: 65 79 Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm & suggested patch test series for clinical use. Contact Dermatitis, 66, 4 19

Orthopedic Implant Allergy 5% of orthopedic implant & up to 21% of patients with preop metal sensitivity may develop cutaneous allergic reactions on reexposure to the same metal Clinical manifestations Cutaneous localized: eczematous reaction overlying implant (urticaria & vasculitis reported) generalized both Non Cutaneous Reactions Implant Failure Basko-Plluska JL, Thyssen, JP & Schalock PC. Cutaneous & Systemic Hypersensitivity Reactions to Metallic Implants.Dermatitis, 2011.22:65 79 Niki Y, Matsumoto H, Otani T, et al. Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty. Biomaterials 2006;26:1019 26

Prospective Longitudinal Studies and Reviews Study Pt Conclusions Carlsson & Mo ller 1989 Thyssen et al, 2009 18 Metal allergic pts with confirmed allergy to metal to metal in their in their device device prior prior to stainless to stainless steel orthopedic steel orthopedic implants had implants no issues had no (6-yr issues ff-up) (6-yr ff-up) 356 Risk of surgical revision not not increased in patients in patients with with metal metal allergies allergies Niki et al 2006 92 26% had (+) LST tests to at least one metal (Ni, Co, Cr, Fe) 5% of total study developed cutaneous allergic reactions In metal (+) prior to implant: 21% developed dermatitis at site of implant (some widespread) Eben et al 2010 92 66/92 had sx (pain, reduced motion, swelling) Rates of allergy: nickel: 24.2% vs 3.8% (no Sx); cobalt: 6.1%; vs 3.8% Symptomatic (31.8%) had allergic reaction to bone cement components Braathen et al 16 81% of failed metal-on-metal implants had metal sensitivity (PT &/or LTT) Hallab N, et al 2001 Accumulated reports in total hip arthroplasty: prevalence of metal allergy ~ 25% in well-functioning vs. ~ 60% in failed/poorly functioning implant Carlsson A, Mo ller H. Implantation of orthopaedic devices in patients with metal allergy. Acta Derm Venereol 1989;69:62 6 Thyssen JP, Jakobsen SS, Engkilde K, et al. The association between metal allergy, total hip arthroplasty, and revision. Acta Orthop 2009;80:646 52 Merritt K, Rodrigo JJ. Immune response to synthetic materials.sensitization of patients receiving orthopaedic implants. Clin Orthop 1996;326:71 9 Niki Y et al. Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty. Biomaterials 2006;26:1019 26. Eben R et al. Contact allergy to metals and bone cement components in patients with intolerance of arthroplasty. Dtsch Med Wochenschr 2010;135:1418 22. Thomas P, et al. Increased metal allergy in patients with failed metal-on-metal hip arthroplasty & periimplant T-lymphocytic inflammation. Allergy 2009;64:1157 65 Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am 2001;83:428 36.

Allergic Contact Dermatitis from bone cement components Reported in 24.8% of patients (n = 239)* Common Bone Cement Allergen in Total Joint Arthroplasties Use Approx % (+) Reaction N,N-dimethyl-p-toluidine (DPT) Reaction initiator 10 Polymethyl methacrylate (MMA) Cement Base 25 Benzoyl Peroxide Activator 8-10 Hydroquinone MMA Stabilization 5 Gentamycin Antibiotic 17-24 Common causes of failure: infection, recurrent dislocation, aseptic osteolysis, fractures *Thomas P, Schuh A, Eben R, et al. Allergy to bone cement components. Orthopa de 2008;37:117 20 Haddad FS, Cobb AG, Bentley G, et al. Hypersensitivity in aseptic loosening of total hip replacements. The role of constituents of bone cement. J Bone Joint Surg Br 1996;78:546 9 Kuehn KD, Ege W, Gopp U. Acrylic bone cements: composition and properties. Orthop Clin North Am 2005;36:17 28

Endovascular stent & In-stent restenosis Study Positive Findings Negative Findings Köster R, Köster R, et al 2000 et al 2000 Prospective Prospective study study Iijima R, Iijima R, et al 2005 et al 2005 Prospective Prospective study study Thyssen, et al 2012 Linkage Study Coronary in-stent Coronary in-stent restenosis 6 mos post restenosis mos post stent & PT 2 mo after stent PT mo after angioplasty angioplasty 174 stented patients 174 stented patients -109 (initial placement) -109 (initial placement) - 65 (restenosis) 65 (restenosis) 149/18,794 (0.8%) PT prior to metal stent placement (+) PT in 10/131 (8%) (+) PT in 10/131 (8%) - All 10 (100%) had in-stent All 10 (100%) had in-stent restenosis restenosis Recurrence of ISR: higher (+) PT Recurrence of ISR: higher (+) to metals (39% vs.12%; p =0.02) PT to metals (39% vs.12%; p =0.02) Predictors of recurrent restenosis: Predictors of recurrent restenosis: (+) patch test (OR 4.39, p =0.02) (+) patch test (OR 4.39, =0.02) However, 57% of of (-) (-) PT PT However, 57% of (-) PT had ISR had ISR Initial stent implantation Initial stent implantation not significantly different not significantly between with or w/o different between with or restenosis (10% vs 9%) w/o restenosis (10% vs 9%) 14% (21/149) had ISR - Only 11.8% (2 /21) had metal allergy Gold-plated stents (thought to be inert), subsequently showed that gold in cardiac stents was a strong risk factor for ISR, especially in those with prior gold allergy * Köster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis Lancet 2000;356:1895 7 Iijima R et al. The impact of metallic allergy on stent implantation: metal allergy & recurrence of in-stent restenosis Int J Cardiol 2005;104:319 25 Thyssen J P et al. G H No association between metal allergy and cardiac in-stent restenosis in patients with dermatitis results from a linkage study. Contact Dermatitis 2011: 64: 138 141. *Svedman C et al. A correlation found between contact allergy to stent material and restenosis of the coronary arteries. Contact Dermatitis 2009: 60: 158 164

Pacemakers/Defibrillators Majority of reactions are infections Allergic complications rare: ~30 cases reported in literature Ti alloy shell: most frequent Manifestations: dermatitis localized above implant impaired wound healing generalized or remote dermatitis (uncommon) Schalock et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 66, 4 19 HonariG, et al. Hypersensitivity reactions associated with endovascular devices. Contact Dermatitis 2008: 59: 7 22 Hallab N J, Jacobs J J. Biologic effects of implant debris. Bull NYU Hosp Jt Dis 2009: 67: 182 188 Oprea M L, Schn oring H, Sachweh J S, Ott H, Biertz J, Vazquez-Jimenez J F. Allergy to pacemaker silicone compounds: recognition and surgical management. Ann Thorac Surg 2009: 87: 1275 1277

Dental Implants & Orthodontic Devices Potential allergen groups Ni palladium &/or Ti alloys CoCrMo alloys Epoxy & epoxy-acrylate preparations Anesthetics & flavorings Flexible titanium-nickel arch wires release more nickel compared to stainless steel Nickel: most common contact allergen to orthodontics Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 66, 4 19

Gynaecological devices Mostly from contraceptive devices contain copper Reports of systemic allergic dermatitis resolving with IUCD removal Contraindication to placement Copper allergy in Copper IUCDs (Paragard)* Ni allergy in Nitinol (Essure)** *Paragard. Product description. Available at: http://www.paragard.com/hcp/aboutparagard/product-description (last accessed 3 December 2010). ** Essure. Instructions for use. Available at:http://www.essuremd.com/portals/essuremd/pdfs/topdownloads/l3002% 2009_09_09%20smaller.pdf (last accessed 28 January 2011).

Should allergy screening be performed? Patients with no history of metal hypersensitivity need not be screened prior to implantation Pre-implantation PT identifies metal-allergic individuals* Screening prior to surgery is recommended for those with history of metal sensitivity of a magnitude sufficient to cause concern to the patient or healthcare provider ** Post-implantation PT: joint pain, implant loosening, or unexplained cutaneous reaction at the implant site with a question of metal hypersensitivity Schalock1, et al. Hypersensitivity reactions to metallic implants diagnostic algorithm & suggested patch test series for clinical use. Contact Dermatitis, 66, 4 19 *Reed K B, et al. Retrospective evaluation of patch testing before or after metal device implantation. Arch Dermatol 2008: 144: 999 1007 **ThyssenJP,Menn e T, Schalock P C, Taylor J S, Maibach H I. Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopaedic implants before and after surgery. Br J Dermatol 2011: 164:473 478

What is the benefit of the medical history? An alternative view The validity of self reported nickel allergy* Sensitivity : 37 82% Specificity: 77 87% Suggests that patient s history is not sufficiently predictive to warrant PT & that the prevalence of reactions is high enough to warrant pre-implant evaluation ** requires all patient who will undergo pectus surgery to be tested for allergies to the metallic component of the implanted surgical stainless steel pectus bar *Schalock et al Hypersensitivity reactions to metallic implants diagnostic algorithm & suggested patch test series for clinical use. Contact Dermatitis, 66, 4 19 * Fors R, et al. Nickel allergy prevalence in a population of Swedish youths from patch test and questionnaire data. Contact Dermatitis 2008: 58: 80 87 *Fleming C J et al. Accuracy of questions related to allergic contact dermatitis. Am J Contact Dermat 2000: 11: 218 221. * Dotterud L K, Falk E S. Metal allergy in north Norwegian schoolchildren and its relationship with ear piercing and atopy. Contact Dermatitis 1994: 31: 308 313. **Kieffer M. Nickel sensitivity: relationship between history and patch test reaction. Contact Dermatitis 1979: 5: 398 401.

Patch Testing vs. Lymphocyte Transformation Test Measures lymphocyte proliferation (stimulation index) after 7 days incubation +/- allergen Limited allergens, availability & rapid decay of T cells (rapid transportation) *? LTT better reflect immune reactions within the body, whereas PT reflects cutaneous reactivity May be useful in questionable cases 54/56 patients with Ti implants, (-) PT & (+) Ti LTT whose systemic symptoms resolved after implant removal Needs Validation *(MELISA test: Health Diagnostics and Research Institute, South Amboy, NJ) Muller K E, Valentine-Thon E. Hypersensitivity to titanium: clinical & laboratory evidence. Neuro Endocrinol Lett 2006: 27: 311 313

What to test with PT with limited allergens is not recommended as there may be multiple causes of the dermatitis Baseline series [NACD, ACDS, European Baseline Series etc] Extended series & specialty trays Extended NA standard series (Chemotechnique or Allergeaze; SmartPractice, Calgary,AB,Canada) International Comprehensive Baseline series (Chemotechnique) Metals Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 2011. 66, 4 19

Mayo Clinic PT Protocol for patients about to or have undergone device implantation Rationale: 1. Implanted devices contain metals nickel, cobalt, chromium, titanium 2. ~ 10% of the general population have cutaneous metal hypersensitivity 3. Cutaneous reactions to metal implants have been documented 4. Hip prostheses have a shorter lifespan in patients with documented sensitization to bone cement 5. Pre implantation PT may guide the choice of the device implanted Reed, et al, Retrospective Evaluation of Patch Testing Before or After Metal Device Implantation. Arch Dermatol. 2008. 144; 8

Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 2011, 66, 4 19

Suspect Orthopedic Metal Implant Allergy Pre Implant Post Implant No Hx of Dermatitis Hx of Dermatitis No Symptoms Symptoms No Concern for Hypersensitivity Reaction Possible Hypersensitivity Reaction Extended Series Metals Implant Test Disc No Testing Extended Series Metals Bone Cement Implant Disc LTT? No Testing Baseline Series Metals: Aluminum, Chromium, Cobalt. Iron, Manganese, Molybdenum, Nickel, Niobium, Silicon, Phosphorus,Tantalum, Titanium, Tungsten, Vanadium Zirconium, Gold, Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 2011 66, 4 19

Orthopedic Metal Implant Allergy + Metal Test No Symptoms No Intervertion No + Symptoms Is Device Removal Necessary? Yes Is removal safe and reasonable Yes No Options Remove Implant Replace w/ non allergenic alloy Coat metal w/ polytetrafluoroethylene No surgical intervention (+) dermatitis: consider 21 day course of tapered oral prednisone Schalock1, et al Hypersensitivity reactions to metallic implants diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis, 2011 66, 4 19

METAL IMPLANT ALLERGY What do we know Metal implant release metal ions and elicit an immune response Most reactions to metal implants are based on case reports or relatively small cohorts ~ 5% developed eczematous reactions directly associated with metallic implants proven cases incriminate nickel, cobalt, chromium, copper The temporal & physical evidence leaves little doubt that a considerable number of patients develop metal sensitivity & cutaneous allergic dermatitis in association with metallic orthopedic implants Basko-Plluska JL, Thyssen, JP & Schalock PC. Cutaneous &Systemic Hypersensitivity Reactions to Metallic Implants. Dermatitis, 2011. 22;2: 65 79 *Niki Y, Matsumoto H, Otani T, et al. Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty. Biomaterials 2006;26:1019 26. **Merritt K, Rodrigo JJ. Immune response to synthetic materials. Sensitization of patients receiving orthopaedic implants. Clin Orthop 1996;326:71 9.

METAL IMPLANT ALLERGY What do we know about Patch Testing Need for patch testing is controversial, poorly reliable in predicting or confirming implant reaction Preimplantation PT: Consider if history of metal sensitivity is of sufficient cause of concern to patient or healthcare provider ** Post cutaneous eruption PT : consider with an appropriate series Basko-Plluska JL et al. Cutaneous &Systemic Hypersensitivity Reactions to Metallic Implants. Dermatitis, 2011. 22;2: 65 79 *Niki Y, Matsumoto H, Otani T, et al. Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty. Biomaterials 2006;26:1019 26. **Merritt K, Rodrigo JJ. Immune response to synthetic materials. Sensitization of patients receiving orthopaedic implants. Clin Orthop 1996;326:71 9. Clinical Campus of Stony Brook University School of Medicine

METAL IMPLANT ALLERGY What else do we know (-) PT is reassuring for absence of delayed hypersensitivity A (+) PT does not prove relevance If relevant allergens are identified & corticosteroid therapy is insufficient to clear eruption, removal of implant may be considered Clinical Campus of Stony Brook University School of Medicine

What we do NOT know about Metal Implant Allergy Whether risk of allergic reaction to orthopedic implants increase in metal sensitized individuals Whether supposed allergies to implanted devices really cause problems such as loosening or dermatitis How to identify the subgroup of metal allergic patients with increased risk of complications from metal implant Whether PT can truly detect reactions to implanted devices Patch Testing vs. Lymphocyte Transformation Test Based on the complex findings, it is difficult to make general principles for good clinical practice & prospective longitudinal studies are strongly needed