ORIGINAL RESEARCH

Topical for Treatment-Resistant Atopic Dermatitis

Nwanneka Okwundu, DO; Leah A. Cardwell, MD; Abigail Cline, MD, PhD; Emily L. Unrue, BS; Irma M. Richardson, MHA; Steven R. Feldman, MD, PhD

a phenomenon known as tachyphylaxis. The pathophysi- PRACTICE POINTS ology of tachyphylaxis to topical corticosteroids has been 3 • Mid-potency corticosteroids are the first-line treat- ascribed to loss of receptor function, but 3,4 ment of atopic dermatitis (AD). the evidence is weak. Patients with severe treatment- • Atopic dermatitis may fail to respond to topical resistant AD improve when treated with mid-potency corticosteroids initially or lose response over time, a topical in an inpatient setting; therefore, treat- phenomenon known as tachyphylaxis. ment resistance copyto topical corticosteroids may be largely 5 • Nonadherence to medication is the most likely cause due to poor adherence. of treatment resistance in patients with AD. Patients with treatment-resistant AD generally improve when treated with topical corticosteroids under condi- tions designed to promote treatment adherence, but this improvementnot often is reported for study groups, not indi- Although topical corticosteroids are the mainstay of treatment of vidual patients. Focusing on group data may not give a atopic dermatitis (AD), these medications may lose efficacy over clear picture of what is happening at the individual level. time, a phenomenon known as tachyphylaxis. However, the underly- In this study, we evaluated changes at an individual level to ing mechanism for tachyphylaxis may be due to lack of treatmentDo adherence rather than loss of efficacy of topical corticosteroids. In determine how frequently AD patients who were previously this study, we aimed to determine if AD patients who were previously treated with topical corticosteroids unsuccessfully would unsuccessfully treated with topical corticosteroids would respond to respond to desoximetasone spray 0.25% under conditions desoximetasone spray 0.25% under conditions designed to promote designed to promote good adherence over a 7-day period. good adherence over a 7-day period. At baseline, patients were randomized to receive either twice-daily telephone calls to discuss Methods treatment adherence (intervention group) or no telephone calls (control This open-label, randomized, single-center clinical study group) during the study period. The patients improved rapidly. In most patients, treatment-resistant AD is CUTISmost likely due to poor adherence included 12 patients with AD who were previously to treatment rather than loss of drug responsiveness. Cutis. 2018;102:205-209. NEW PODCAST Dr. Steven R. Feldman discusses topical corticosteroids for treatment-resistant atopic dermatitis with Cutis topic dermatitis (AD) is most often treated with Editor-in-Chief Vincent A. DeLeo, MD, in a new episode mid-potency topical corticosteroids.1,2 Although of the “Peer to Peer” podcast. A this option is effective, not all patients respond to >> http://bit.ly/2n9VsHO treatment, and those who do may lose efficacy over time,

From the Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, North Carolina. Dr. Feldman also is from the Departments of Pathology and Social Sciences & Health Policy. This study was funded by Taro Pharmaceutical Industries Ltd. Drs. Okwundu, Cardwell, and Cline; Ms. Unrue; and Ms. Richardson report no conflict of interest. Dr. Feldman has received consulting, research, and/or speaking support from Sun Pharmaceutical Industries Ltd and Taro Pharmaceutical Industries Ltd. He also is part owner of Causa Research. The eFigure is available in the Appendix online at www.mdedge.com/cutis. Correspondence: Nwanneka Okwundu, DO, Department of Dermatology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1071 ([email protected]).

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unsuccessfully treated with topical corticosteroids in the Department of Dermatology at Wake Forest Baptist TABLE 1. Prior Failed Treatments for Medical Center (Winston-Salem, North Carolina) Atopic Dermatitis (Table 1). The study was approved by the local institu- tional review board. a Patient No. Prior Failed Treatments Inclusion criteria included men and women 18 years 1 , tacrolimus, topical moisturizers or older at baseline who had AD that was considered amenable to therapy with topical corticosteroids by the 4 Desonide, desoximetasone, clinician and were able to comply with the study protocol 5 Desonide (Figure). Written informed consent also was obtained from 6 Tea tree oil, , topical each patient. Women who were pregnant, breastfeeding, moisturizer or unwilling to practice birth control during participa- 7 , doxepin, tion in the study were excluded. Other exclusion criteria acetonide, , hydrocortisone, included presence of a condition that in the opinion of the , topical moisturizers, investigator would compromise the safety of the patient triamcinolone or quality of data as well as patients with no access to a 8 Clobetasol, dapsone, desoximetasone, telephone throughout the day. Patients diagnosed with methotrexate, , triamcinolone/ conditions affecting adherence to treatment (eg, dementia, silver sulfadiazine, topical moisturizers, Alzheimer disease), those with a history of allergy or sen- triamcinolone, UV phototherapy sitivity to corticosteroids, and those with a history of drug 10 Crisaborole, topical anti-itch lotion hypersensitivity were excluded from the study. 11 Desoximetasone, dupilumab, fluocinonide, All 12 patients were treated with desoximetasone methotrexate, pimecrolimus, tacrolimus, spray 0.25% for 7copy days. Patients were instructed not to use triamcinolone other AD medications during the study period. At base- line, patients were randomized to receive either twice- 12 Triamcinolone daily telephone calls to discuss treatment adherence a Patients 2, 3, and 9 were either not reachable or did not remem- (intervention group) or no telephone calls (control) dur- ber prior treatment. ingnot the study period. Patients in both the intervention and control groups returned for evaluation on days 3 and 7. Do

Assessed for eligibility (n=12)

Excluded (n=0)

CUTIS Randomized

Allocated to intervention Allocated to control (n=6) (n=6)

Lost to follow-up (n=0) Lost to follow-up (n=0) Discontinued intervention Discontinued intervention (n=0) (n=0)

Analyzed (n=6) Analyzed (n=6)

Consort diagram.

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During these visits, disease severity was evaluated using TLSS score was 38.3% in the intervention group versus the pruritus visual analog scale, Eczema Area and Severity 9.7% in the control group. The mean improvement in IGA Index (EASI), total lesion severity scale (TLSS), and inves- score was 45.8% in the intervention group versus 4.2% in tigator global assessment (IGA). Descriptive statistics the control group. Only one patient in the control group were used to report the outcomes for each patient. (patient 8) showed lower EASI, TLSS, and IGA scores at baseline. Results Twelve AD patients who were previously unsuccessfully Comment treated with topical corticosteroids were recruited for Although topical corticosteroids are the mainstay for the study. Six patients were randomized to the interven- treatment of AD, many patients report treatment resis- tion group and 6 were randomized to the control group. tance after a period of a few doses or longer.6-9 There Fifty percent of patients were black, 50% were women, is strong evidence demonstrating rapid corticosteroid and the average age was 50.4 years. All 12 patients com- receptor downregulation in tissues after corticosteroid pleted the study. therapy, which is the accepted mechanism for tachy- At the end of the study, most patients showed phylaxis, but the timing of this effect does not match up improvement in all evaluation parameters (eFigure). All with clinical experiences. The physiologic significance 12 patients showed improvement in pruritus visual ana- of corticosteroid agonist-induced receptor downregula- log scores; 83.3% (10/12) showed improved EASI scores, tion is unknown and may not have any considerable 75.0% (9/12) showed improved TLSS scores, and 58.3% effect on corticosteroid efficacy.3 A systematic review (7/12) showed improved IGA scores (Tables 2–5). Patients by Taheri et al3 on the development of resistance to who received telephone calls in the intervention group topical corticosteroids proposed 2 theories for the showed greater improvement compared to those in the underlying pathogenesis of tachyphylaxis: (1) long- control group, except for pruritus; the mean reduction term patient nonadherence,copy and (2) the initial maximal in pruritus was 76.9% in the intervention group versus response during the first few weeks of therapy eventu- 87.0% in the control group. The mean improvement in ally plateaus. Because corticosteroids may plateau after EASI score was 46.9% in the intervention group versus a certain number of doses, natural disease flare-ups 21.1% in the control group. The mean improvement in duringnot this period may give the wrong impression of Do TABLE 2. Pruritus Visual Analog Scale TABLE 3. Eczema Area and Severity Index

Mean Score Mean Score

Improvement Improvement Patient From Patient From No. Baseline Day 3 Day 7 Baseline, % No. Baseline Day 3 Day 7 Baseline, % Intervention Group CUTIS Intervention Group 1 6.5 4 1 84.6 1 0.9 0.45 0.45 50.0 3 3.5 3.5 3 14.3 3 1.5 1.2 1.2 20.0 4 9 3 1 88.9 4 0.6 0.2 0 100 5 1.5 0.5 0 100 5 2.8 1.8 1.6 42.9 6 7.5 3 2 73.3 6 3.6 3.2 3.2 11.1 10 7 1 0 100 10 2.1 1.5 0.9 57.1 Control Group Control Group 2 0.5 0.5 0 100 2 2.1 1.8 1.1 47.6 7 10 5.5 1 90.0 7 1.9 1.35 0.8 57.9 8 8 4 5 37.5 8 0.8 0.8 1.2 −50.0 9 7 1 0 100 9 0.6 0.6 0.4 33.3 11 9 3 0.5 94.4 11 21.6 21.1 13.4 38.0 12 7.5 0 0 100 12 1.6 1.6 1.6 0

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TABLE 4. Total Lesion Severity Scale TABLE 5. Investigator Global Assessment

Mean Score Mean Score

Improvement Improvement From From Patient No. Baseline Day 3 Day 7 Baseline, % Patient No. Baseline Day 3 Day 7 Baseline, %

Intervention Group Intervention Group 1 3 2 1 66.7 1 1 1 0 100 3 3 3 3 0 3 2 2 2 0.0 4 1 1 0 100 4 1 0 0 100 5 10 7 7 30.0 5 4 3 3 25.0 6 15 15 15 0 6 3 3 3 0 10 3 2 2 33.3 10 2 2 1 50.0 Control Group Control Group 2 4 3 3 25.0 2 1 1 1 0 7 2 1 1 50.0 7 2 2 1 50.0 8 2 2 4 −100 8 1 1 2 −100

9 3 3 2 33.3 9 2 copy2 1 50.0 11 12 11 8 33.3 11 4 4 3 25.0 12 6 6 5 16.7 12 2 2 2 0 not

tachyphylaxis.10 The treatment “resistance” reported by and anxiety about using them. Topical corticosteroid the patients in our study may have been due to this phobia may stem from a misconception that these plateau effect or to poor adherence. Doproducts carry the same adverse effects as their oral and Our finding that nearly all patients had rapid improve- systemic counterparts, which may be perpetuated by the ment of AD with the topical corticosteroid is not defini- media.1 Of 200 dermatology patients surveyed, 72.5% tive proof but supports the notion that tachyphylaxis is expressed concern about using topical corticosteroids largely mediated by poor adherence to treatment. Patients on themselves or their children’s skin, and 24% of these rapidly improved over the short study period. The short patients stated they were noncompliant with their med- duration of treatment and multiple visits over the study ication because of these worries. Almost 50% of patients period were designed to help ensure patient adherence. requested prescriptions for corticosteroid-sparing Rapid improvement in AD whenCUTIS topical corticosteroids medications such as tacrolimus.1 Patient education is are used should be expected, as AD patients have rapid important to help ensure treatment adherence. Other improvement with application of topical corticosteroids in factors that can affect treatment adherence include inpatient settings.11,12 forgetfulness; the chronic nature of AD; the need for Poor adherence to topical medication is common. In ongoing application of topical treatments; prohibitive a Danish study, 99 of 322 patients (31%) did not redeem costs of some topical agents; and complexities in coor- their AD prescriptions.13 In a single-center, 5-day, prospec- dinating school, work, and family plans with the treat- tive study evaluating the use of fluocinonide cream 0.1% ment regimen.2 for treatment of children and adults with AD, the median We attempted to ensure good treatment adherence in percentage of prescribed doses taken was 40%, according our study by calling the patients in the intervention group to objective electronic monitors, even though patients twice daily. The mean improvement in EASI, TLSS, and reported 100% adherence in their medication diaries. IGA scores was higher in the intervention group versus Better adherence was seen on day 1 of treatment in which the control group, which suggests that patient remind- 66.6% (6/9) of patients adhered to their treatment strat- ers have at least some benefit. Because AD treatment egy versus day 5 in which only 11.1% (1/9) of patients resistance appears more closely tied to nonadherence used their medication.1 rather than loss of medication efficacy, it seems prudent Topical corticosteroids are safe and efficacious if used to focus on interventions that would improve treatment appropriately; however, patients commonly express fear adherence; however, such interventions generally are not

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well tested. Recommended interventions have included severity, with 100% of patients reporting improvement educating patients about the side effects of topical cor- in pruritus. Intervention to improve treatment adherence ticosteroids, avoiding use of medical jargon, and taking may lead to better health outcomes. When AD appears patient vehicle preference into account when prescribing resistant to topical corticosteroids, addressing adherence treatments.8 Patients should be scheduled for a return visit issues may be critical. within 1 to 2 weeks, as early return visits can augment treatment adherence.14 At the return visit, there can be a REFERENCES more detailed discussion of long-term management and 1. Patel NU, D’Ambra V, Feldman SR. Increasing adherence with topical side effects.8 agents for atopic dermatitis. Am J Clin Dermatol. 2017;18:323-332. 2. Mooney E, Rademaker M, Dailey R, et al. Adverse effects of topical Limitations of our study included a small sample size corticosteroids in paediatric eczema: Australasian consensus state- and brief treatment duration. Even though the patients ment. Australas J Dermatol. 2015;56:241-251. had previously reported treatment failure with topical 3. Taheri A, Cantrell J, Feldman SR. Tachyphylaxis to topical glucocorti- corticosteroids, all demonstrated improvement in only coids; what is the evidence? Dermatol Online J. 2013;19:18954. 1 week with a potent topical corticosteroid. The treat- 4. Miller JJ, Roling D, Margolis D, et al. Failure to demonstrate therapeu- ment resistance that initially was reported likely was due tic tachyphylaxis to topically applied steroids in patients with psoriasis. J Am Acad Dermatol. 1999;41:546-549. to poor adherence, but it is possible for AD patients to 5. Smith SD, Harris V, Lee A, et al. General practitioners knowledge be resistant to treatment with topical corticosteroids due about use of topical corticosteroids in paediatric atopic dermatitis in to allergic contact dermatitis. Patients could theoretically Australia. Aust Fam Physician. 2017;46:335-340. be allergic to components of the vehicle used in topical 6. Sathishkumar D, Moss C. Topical therapy in atopic dermatitis in chil- corticosteroids, which could aggravate their dermatitis; dren. Indian J Dermatol. 2016;61:656-661. however, this effect seems unlikely in our patient popula- 7. Reitamo S, Remitz A. Topical agents for atopic dermatitis. In: Bieber T, ed. Advances in the Management of Atopic Dermatitis. London, tion, as all the patients in our study showed improvement United Kingdom: Future Medicine Ltd; 2013:62-72. following treatment. Another study limitation was that 8. Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence was not measured. The frequent follow-up adherence to topical medication: adherence is very poor in children visits were designed to encourage treatment adherence, with atopic dermatitis. J Am Acad Dermatol. 2007;56:211-216. but adherence was not specifically assessed. Although 9. Fukaya M. homeostasis in the epidermis is influenced by topical corticosteroids in patients with atopic dermatitis. Indian J patients were encouraged to only use the desoximetasone Dermatol. 2017;62:440. spray during the study, it is not known whether patients 10. Mehta AB, Nadkarni NJ, Patil SP, et al. Topical corticosteroids in der- used other products. matology. Indian J Dermatol Venereol Leprol. 2016;82:371-378. 11. van der Schaft J, Keijzer WW, Sanders KJ, et al. Is there an additional Conclusion value of inpatient treatment for patients with atopic dermatitis? Acta Some AD patients exhibit apparent decreased efficacy Derm Venereol. 2016;96:797-801. 12. Dabade TS, Davis DM, Wetter DA, et al. Wet dressing therapy in con- of topical corticosteroids over time, but this tachyphy- junction with topical corticosteroids is effective for rapid control of laxis phenomenon is more likely due to poor treatment severe pediatric atopic dermatitis: experience with 218 patients over adherence than to loss of corticosteroid responsiveness. 30 years at Mayo Clinic. J Am Acad Dermatol. 2011;67:100-106. In our study, AD patients who reported treatment failure 13. Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are with topical corticosteroids improved rapidly with topical never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol. 2008;59:27-33. corticosteroids under conditions designed to promote 14. Sagransky MJ, Yentzer BA, Williams LL, et al. A randomized controlled good adherence to treatment. The majority of patients pilot study of the effects of an extra office visit on adherence and out- improved in all 4 parametersCUTIS used for evaluating disease Do notcomes in atopic copy dermatitis. Arch Dermatol. 2010;146:1428-1430.

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APPENDIX

A B 10 10 10 1044 10 251025

8 88 8 208208 33

6 66 6 156156 22 4 44 4 104104

11 2 22 2 2552 Pruritus Visual Analog Pruritus Scale Visual Analog Pruritus Scale Pruritus Visual Analog Pruritus Scale Visual Analog Pruritus Scale Visual Analog Pruritus Scale Visual Analog Pruritus Scale Eczema Area and Severity Index and Severity Area Eczema Index and Severity Area Eczema 0 0000 Index and Severity Area Eczema Index and Severity Area Eczema 0 000 DayDayDayDay Day0 0 0 00 DayDayDayDay 3 3 33 DayDayDayDay 7 7 77 DayDayDayDay 0 00 0 DayDayDayDay 33 3 3 DayDayDayDay 77 7 7

PatientPatientPatientPatientPatient 1 1 1 11 Patient Patient Patient Patient Patient 3 3 3 33 Patient Patient Patient Patient Patient 4 4 4 44 Patient Patient Patient Patient Patient 5 5 5 55 Patient Patient Patient Patient Patient 6 6 6 66 Patient Patient Patient Patient 10 10 1010 PatientPatientPatientPatient 2 2 22 Patient Patient Patient Patient Patient 7 7 77 Patient Patient Patient Patient 8 8 88 8 Patient Patient Patient Patient Patient 9 99 9 9 Patient Patient Patient Patient Patient 11 1111 11 11 Patient Patient Patient Patient 1212 12 12

10 C 10 D 444 252525

8 8 202020 333 6 6 151515 222 4 1010410 11 copy 11 2 5255 Pruritus Visual Analog Pruritus Scale Visual Analog Pruritus Scale Eczema Area and Severity Index and Severity Area Eczema Index and Severity Area Eczema 0 00 Index and Severity Area Eczema Index and Severity Area Eczema 000 Eczema Area and Severity Index and Severity Area Eczema Index and Severity Area Eczema

00 Index and Severity Area Eczema Index and Severity Area Eczema 00 DayDayDayDay 0 0 00 DayDayDay 3 33 DayDayDayDay 7 77 DayDayDay 0 00 DayDayDayDay 3 33 3 DayDayDayDay 7 77 7

PatientPatientPatient 1 1 1 Patient Patient Patient 3 3 3 Patient Patient Patient 4 4 4 Patient Patient Patient 5 5 5 Patient Patient Patient 6 6 6 Patient Patient 1010 10 PatientPatient 2 2 Patient Patient Patient 7 77 Patient Patient Patient 8 88 Patient Patient Patient 9 9 9 Patient Patient Patient 11 11 11 Patient Patient Patient 12 12 12 PatientPatient 11 Patient Patient 33 Patient Patient 44 Patient Patient 55 Patient Patient 66 Patient Patient 1010 not14 PatientPatient 22 Patient Patient 77 Patient Patient 88 Patient Patient 99 Patient Patient 1111 Patient Patient 1212

12

14 1016 E 10 10 F 44 252512 14 Do 8 8 208 10 12 16 2020 33 10 14 6 15 8 6 12 6 8 1515 22 10 6 6 10 4 8 Scale Lesion Severity Total 4 10410 4 4 6 Total Lesion Severity Scale Lesion Severity Total 5 2 11 4 2 2 Total Lesion Severity Scale Lesion Severity Total 2 55 2

Total Lesion Severity Scale Lesion Severity Total 2 0 0 Pruritus Visual Analog Pruritus Scale 0 0 Visual Analog Pruritus Scale 0 0 Eczema Area and Severity Index and Severity Area Eczema Index and Severity Area Eczema 00 Day 0 Day 3 Day 7 0 Index and Severity Area Eczema Index and Severity Area Eczema 00 Day 0 Day 3 Day 7 DayDayDay 0 00 Day 0DayDayDay 3 33 Day 3 DayDayDay 7 77 Day 7 DayDayDay 00 0 DayDayDayDay 3 33 3 DayDayDay Day7 77 7

Patient 1 PatientPatient 3 1 Patient 4CUTISPatient Patient3 Patient5 4 Patient Patient 6 5 Patient Patient 6 10 Patient 10 Patient Patient2 2 Patient Patient 7 7 Patient 8 8 Patient Patient 9 9 Patient 11 Patient Patient 11 12 Patient 12 PatientPatientPatient 1 11 Patient Patient Patient 3 33 Patient Patient Patient 4 44 Patient Patient Patient 5 55 Patient Patient Patient 6 66 Patient Patient Patient 10 1010 PatientPatientPatient 2 22 Patient Patient Patient 77 Patient Patient 8 88 Patient Patient Patient 99 9 Patient Patient Patient 1111 11 Patient Patient Patient 1212 12

G H 4.5 4.5 4.5 4.5 10 10 4 44 25254 4 3.5 3.5 3.5 3.5 8 20820 3 33 3 3

2.5 62.5 2.515615 2.5 2 22 2 2 1. 5 41. 5 1.104 510 1. 5 1 1 1 1 11 2 2 0.5 0.5 0.555 0.5 Investigator Global Assessment Investigator Global Assessment Investigator Global Assessment Investigator Global Assessment Investigator

0 Visual Analog Pruritus Scale 0 Visual Analog Pruritus Scale 0 0 Eczema Area and Severity Index and Severity Area Eczema Index and Severity Area Eczema 0 00 Index and Severity Area Eczema Index and Severity Area Eczema 000 DayDay 0DayDayDay 0 00 0 DayDay DayDay3 Day 3 33 3 DayDay DayDay7 Day7 77 7 DayDayDay 00 Day 0 DayDayDayDay 33 33 Day 3 DayDayDay 77 7 Day 7

Patient 1PatientPatientPatientPatient 11 Patient 11 Patient3 Patient Patient Patient 3 3 Patient 33 Patient4 Patient Patient Patient 4 4 44 Patient Patient 5 Patient Patient Patient 5 5 55 Patient Patient Patient Patient 6 Patient 6 66 6 Patient Patient Patient Patient 10 Patient 10 1010 10 PatientPatientPatientPatient 2Patient 2 22 2 Patient Patient Patient Patient 7 Patient 77 7 Patient Patient Patient 8 Patient 8 88 8 Patient Patient Patient Patient 9 99 Patient9 9 Patient Patient Patient 1111 11 Patient Patient Patient 11 Patient 1212 12 Patient 12

eFIGURE. Evaluation of atopic dermatitis severity in the intervention versus control groups using the pruritus visual analog scale (A and B), Eczema Area and Severity Index (C and D), total lesion severity scale (E and F), and investigator global assessment (G and H).

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