2/5/2018

What to do When Patch Testing is Negative

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY

Michael Sheehan, MD

Michael P. Sheehan, MD Dermatology Physicians Inc. Columbus, IN

U019-What to do When Patch Testing is Negative DISCLOSURES Celgene: Speaker Bureau

“Patch Test Negative Dermatitis”

Potential False Negative Results T.R.U.E Test versus Expanded Patch Testing

Inflammatory skin condition consistent with acute, subacute or chronic dermatitis.

Potential for false negative reactions – Fragrance mix, balsam of Peru, thiuram, carba mix

Adequate patch testing failed to show positive allergen or current relevance. Often dealing with CHRONIC and GENERALIZED dermatitis.

Sheretz 2001

Potential False Negative Results

Potential False Negative Results

Testing to Standard Mixes versus Individual Allergens

Reading Time

Patch testing with standard mixes may miss patients allergic to an individual allergen in the mix.

EXAMPLES:

Day 1

Day 2

0 hr

24 hr

Place Allergens

Fragrance Mix

Photopatch

Day 3 48 hr Remove Allergens

Standard 5 Day Reading Protocol

MCI/MI Thiourea Mix

2-5

Day 5

Day 7

96 hr

144 hr

Standard Read

Day 10

216 hr Delayed Read Metals Corticosteroids Neomycin PPD Gallates Epoxy Resins

6-10

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Testing to Non-standardized Allergens Skin testing to oral medications can be of value in patients with cutaneous adverse drug reactions (CADR) but must be interpreted cautiously. False positive reactions may be irritant reactions related to additives such as sodium lauryl sulfate or due to low pH.

Sensitivity varies but has been reported to be 50% for patch testing and 65% for intradermal testing in patients with CADR in which a single drug was favored as the cause.

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Other Etiologies • • • • • • • • • •

Irritant Contact Dermatitis Atopic Dermatitis Seborrheic Dermatitis Nummular Dermatitis Neurodermatitis Chronic Eczematous Eruption of the Aged Eczematized Psoriasis Pityriasis Rubra Pilaris Dermatomyositis Non-bullous pemphigoid

• • • • • • • • •

Consider Further Work-Up Scabies CTCL Tinea Xerosis Drug Reaction Urticaria Grover’s Disease Dermatitis Herpetiformis Pruritus

• • • • • • • • • • •

Full review of systems Comprehensive exam/lymph node survey Test for dermatographism Skin biopsy (H&E / DIF) CBC with differential Thyroid function panel Comprehensive metabolic panel KOH Scabies prep HIV Stool ova & parasite

• • • • •

Tissue transglutaminase Iron studies Age appropriate malignancy screening CXR SPEP / immunofixation

Stepwise Dermatitis Management

Topical Corticosteroids (TCS) Recalcitrant severe dermatitis

Systemic Therapy (Corticosteroids, MTX, Mycophenolate mofetil, CsA, AZA) Phototherapy

Moderate to severe dermatitis Mild to moderate dermatitis

Phototherapy Mid-high potency topical corticosteroids Topical calcineurin inhibitors Phototherapy Low potency topical corticosteroids Topical calcineurin inhibitors

Mild dermatitis Skin hydration, emollients, irritant avoidance, antihistamines for pruritus

Modified from Akdis C.A., Akdis M., Bieber T., et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report. Allergy. 2006;61:969-987.

• •

Inhibit T-cell activation and leukocyte migration Avoid “static” treatment regimens

Rescue Therapy • Use during acute flares • Higher potency and increased frequency of application • Limits set on use BID for 2 weeks

Suppressive Therapy • Use on “hot spots” intermittently during quiescent times

Low potency TCS or TCI twice a week 23,24

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Topical PDE-4 Inhibitors

Topical Calcineurin Inhibitors (TCI) Agents:

Tacrolimus 0.03% or 0.1% ointment Pimecrolimus 1% cream

Agents:

Crisaborole 2% Ointment

• FDA approval for atopic dermatitis

• Inhibit T-cell and dendritic cell activation

• Anti-inflammatory non-steroidal phosphodiesterase 4 inhibitor

• Both have been shown capable of suppressing allergic and irritant contact dermatitis. • May play a role in both rescue and suppressive regimens. • Anti-pruritic effects as well as burning dysesthesia with application may be due to neuropeptide release and depletion similar in mechanism to capsaicin. 25,26

Antimicrobial Therapy

Antihistamines FIRST GENERATION H1 ANTAGONISTS

Topical

Agents:

• Dilute bleach baths • Chlorhexidine / Mupirocin

• •

• The combination of a topical antibiotic along with a topical corticosteroid has been shown to be more effective than topical corticosteroids alone in atopic dermatitis.

Diphenhydramine / Hydroxyzine

Often overlooked important adjuvant therapy Soporific effect is important therapeutically for restful sleep

SECOND GENERATION H1 ANTAGONISTS Agents: • •

Cetirizine / Levocetirizine / Loratadine / Desloratadine / Fexofenadine

Can be used during daytime due to less sedation Less effective in controlling pruritus

21,22

Systemic Corticosteroids Clinical Pearls • Rule of thumb  Consider if >20% BSA involved or severe facial / genital / hand involvement • Use caution in patients at risk for volume over load

Methotrexate • Limits lymphocyte proliferation leading to immunosuppressive and antiinflammatory effects.

• Extensive literature available in management of various types of dermatitis. • Similar efficacy to azathioprine with more desirable safety profile. • Monitor for hepatoxicity.

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Azathioprine

Cyclosporine • Systemic calcineurin inhibitor.

•

Systemic immunosuppressant / purine analog.

•

Undergoes a complex metabolism involving the enzyme thiopurine methyl tansferase (TPMT).

•

Considered second-line therapeutic option for severe atopic dermatitis.

•

Steroid sparing agent with slower onset than cyclosporine.

•

Potential for myelosuppression, hepatotoxicity, gastrointestinal disturbances, infections, and neoplasia including potential for NMSC and lymphoma.

• Primary benefit is ability for rapid onset. • Well established in the literature for the management of severe dermatitis. • Potential for nephrotoxicity, hypertension, and neoplasia limit long term use. • Risk of nephrotoxicity increases with doses above 5mg/kg/day, treatment duration greater than 4 months, or increase in creatinine greater than 30% above baseline. 32-37

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Phototherapy (UVA, UVB)

Mycophenolate Mofetil

Narrowband UVB

• Selectively and noncompetitively inhibits inosine monophosphate dehydrogenase in the de novo purine synthesis pathway.

• Has been shown experimentally to suppress contact hypersensitivity reactions in mice. • Long record of efficacy in management of moderate to severe atopic dermatitis.

• More acceptable for chronic use when compared to cyclosporine. • Dose dependent gastrointestinal side effects.

PUVA

• Potential for miscarriage and teratogenicity (Mycophenolate REMS).

• May be of particular benefit for refractory hand dermatitis.

• Less literature available in management of dermatitis.

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Apremilast

Dupilumab

• Inhibits PDE4 leading to increased levels of cAMP, decreased production of TNF-alpha, and increased levels of IL-10.

• Monoclonal antibody against the IL4 receptor alpha subunit

• Limited studies available to suggest safety and efficacy in atopic dermatitis.

• FDA approved for severe adult atopic dermatitis

• Blocks signaling of IL4 and IL13

apremilast Proinflammatory cytokines TNF-alpha

Anti-inflammatory cytokines IL-10 38,39

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Citations

Citations 13.

1.

2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12.

Sheretz EF, Fransway AF, Belsito DV, DeLeo VA, Fowler JF, Maibach HI, Marks JG, Mathias T, Pratt MD, Rietschel RL, Taylor JS. Patch testing discordance alert: False-negative findings with rubber additives and fragrances. Journal of the American Academy of Dermatology 2001;45(2):313-314. De Groot et al. Frequency of false-negative reactions to the fragrance mix. Contact Dermatitis 1993;28:139-140. Mann et al. Baseline series fragrance markers fail to predict contact allergy. Contact Dermatitis 2014;70(5):276-281. Castanedo-Tardana Mari , Zug K. Methylisothiazolinone. Dermatitis 2013;24(1):2-6. Militello G, Marcus R. Dialkyl thioureas. Dermatitis 2008;19(5):E42-E43. Davis MD, Bhate K, Rohlinger AL, Farmer SA, Richardson DM, Weaver AL. Delayed patch test reading after 5 days: The Mayo Clinic experience. Journal of the American Academy of Dermatology 2008;59(2):225-233. Isaksson M, Andersen KE, Brandao FM, Bruynzeel DB, Bruze M, Camarasa JG, et al. Patch testing with corticosteroid mixes in Europe: a multicentre study of the EECDRG. Contact Dermatitis 2000;42:27-35. Hillen U, Jappe U, Frosch PJ, Becker D, Brasch J, Lilie M, et al. German Contact Dermatitis Research Group. Late reactions to the patch-test preparations para-phenylenediamine and epoxy resin: a prospective multicentre investigation of the German Contact Dermatitis Research Group. Br J Dermatol 2006;154:665-70. Jonker MJ, Bruynzeel DP. The outcome of an additional patch-test reading on days 6 or 7. Contact Dermatitis 2000;42:330-5. Geier J, Gefeller O, Wiechmann K, Fuchs T. Patch test reactions at D4, D5 and D6. Contact Dermatitis 1999;40:119-26. Barbaud et al. Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions. Contact Dermatitis 2001;45:265268. American Contact Dermatitis Society. Statement on patch testing.

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Hoeck UL More T.R.U.E Test allergens are needed. J Am Acad Dermatol. 2005 Mar; 51. Belsito DV, et al. Patch testing with a standard allergen ("screening") tray: rewards and risks. Dermatol Ther. 2004;17 (3):231-9. Nettis E, et al. Results of standard series patch testing in patients with occupational allergic contact dermatitis. Allergy. 2003 Dec; 58(12):1304-7. Saripalli YV, et al. The detection of clinically relevant contact allergens using a standard screening tray of twenty-three allergens. J Am Acad Dermatol. 2003 Jul; 49(1):65-9. Suneja T, et al. Comparative study of Finn Chambers and T.R.U.E test methodologies in detecting the relevant allergens inducing contact dermatitis. J Am Acad Dermatol. 2001 Dec; 45(6 pt 1):836-9. Katsarma G, et al. Suspected fragrance allergy requires extended patch testing to individual fragrance allergens. Contact Dermatitis. 1999 Oct; 41(4):193-7. Larkin A, et al. The utility of patch tests using larger screening series of allergens. Am J Contact Dermat. 1998 Sept; 9(3):142-5. Cohen DE, et al. Utility of standard allergen series alone in the evaluation of allergic contact dermatitis: a retrospective study of 732 patients. J Am Acad Dermatol. 1997 Jun; 36(6 pt 1):914-8. Akdis C.A., Akdis M., Bieber T., et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report. Allergy. 2006;61:969-987. Leyden JJ, Kligman AM. The case for steroid-antibiotic combination. Br J Dermatol 1977;96:179–87. Wollenberg A, Sidhu MK, Odeyemi I, et al. Economic evaluation of maintenance treatment with tacrolimus 0.1% ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol. 2008;159(6):1322-1330. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy. 2008;63(6):742-750.

Citations 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

Lauerma AI, Stein BD, Homey B, et al. Topical FK 506: suppression of allergic and irritant contact dermatitis in the guine pig. Arch Dermatol Res 1994;286:337. Pereira U, Boulais N, Lebonvallet N, Pennec JP, Dorange G, Misery L. Mechanisms of the sensory effects of tacrolimus on the skin. British Journal of Dermatology. 2010;163(1):70-7. Shintani Y, Yasuda Y, Kobayashi K, Maeda A, and Morita A. Narrowband ultraviolet B radiation suppresses contact hypersensitivity. Photodermatology, Photoimmunology & Photomedicine. 2008;24(1):32-7. Warshaw E. Therapeutic options for chronic hand dermatitis. Dermatologic Therapy. 2004;17:240-50. Schram ME, Roekevisch E, Leeflang MM, et al. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol. 2011;128:353–359. Egan CA, Rallis TM, Meadows KP, et al. Low-dose oral methotrexate treatment for recalcitrant palmoplantar pompholyx. J Am Acad Dermatol. 1999;40: 612–614. Denby KS. Beck LA. Update on systemic therapies for atopic dermatitis. Current Opinion in Allergy & Clinical Immunology . 2012;12(4):4216. Roekevisch E. Spuls PI. Kuester D. Limpens J. Schmitt J. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review. Journal of Allergy & Clinical Immunology. 133(2):429-38, Feb 2014. Granlund H, Erkko P, Reitamo S. Long-term follow-up of eczema patients treated with cyclosporine. Acta Derm Venereol 1998;78:40. Lakshmi C. Srinivas CR. Jayaraman A. Ciclosporin in parthenium dermatitits-a report of 2 cases. Contact Dermatitis . 2008:59(4);245-8. Munro CS, Levell NJ, Shuster S, Friedmann PS. Maintenance treatment with cyclosporin in atopic eczema. Br J Dermatol 1994;130:376-80. Sowden JM, Berth-Jones J, Ross JS, Motley RJ, Marks R, Finlay AY, et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991;338:137-40. Griffiths CEM, Dubertret L, Ellis CN, et al. cyclosporine in psoriasis clinical practice: an international consensus statement. Br J Dermatol 2004;150:11-23.

Citations 38. 39.

Volf EM, Au SC, Dumont N, Scheinman P, Gottlieb AB. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol. 2012;11(3):341-346. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890-897.

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