Topical immunomodulation. Charoen Choonhakarn,MD Division of Dermatology Khon Kaen University

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1 Topical immunomodulation Charoen Choonhakarn,MD Division of Dermatology Khon Kaen University

2 Vitiligo

3 Atopic dermatitis

4 Seborrheic dermatitis

5 Oral lichen planus

6 Anogenital warts

7 Bowen s disease actinic keratosis

8 Malignant melanoma

9 Basal cell carcinoma

10 Side effects

11 Topical immunotherapy Immune response modifier Immunomodulator

12 Immune system -Innate immune system phagocytic cells to recognized pathogen natural killer cells (NK) -Adaptive or acquired immune system recognition of foreign Ag by major histocompatibility complex (MHC) I,II and by Agpresenting cell (Langerhans cells)

13 Topical immunomodulation Proinflammatory agents: Toll-like receptor (TLR) agonist, interferon; boost innate and acquired immune response/shifting the balance of T- helper1/t-helper2 (Th1/Th2) Immunosuppressive agents: corticosteroids, anti-tnf agents, anti- CD4+T cell agents

14 Topical immunomodulation Immune enhancers Obligate contact allergens Dinitrochlorobenzene (DNCB) Diphencyprone (DCP) Squaric acid dibutyl ester (SADBE) Toll-like receptor (TLR) agonist Imiquimod 5% Resiquimod Immunosuppressive agents Topical corticosteroids Calcineurin inhibitors: macrolactam Tacrolimus 0.03%,0.1% Pimecrolimus 1% Mycophenolate mofetil

15 Toll-receptor Toll receptor : fruit fly, Drosophila melanogaster, antifungal defense Family of type I transmembrane TLR express on APCs (macrophages, dendritic cells) : innate immune system Engagement of TLRs with their ligands elicits a pathogen-specific cellular immune response Provoke proinflammatory and antimicrobial response eg. cytokines, chemokines

16 Toll-receptor This stimulation depends on protein MyD88 MyD88+protein kinase+transcription factor activates NF-ĸB, then produces key cytokines eg. IFN-α, TNF-α, IL-1,6,12 TLRs detected in human neutrophils, macrophages, dendritic, dermal endothelial, mucosal epithelial, B and T cells Alert the immune system to the presence of a pathogen

17 CD4+ cells recognize Ag in association with MHC class II Th 1 cytokines induce cell-mediated or innate immunity (IL-2, IFN-γ, TNF-β) Th 2 cytokines induce humoral immunity (IL-4,5,6,9,10,13)

18 Toll-like receptor (TLR)

19 Toll-like receptor (TLR)

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21 Immunosuppressive agents Cyclosporin: cyclosporin-cyclophilin complex: calcineurin inhibition blocks NF-AT binding IL-2 gene promotor: suppress T-cell activation and proliferation Tacrolimus, pimecrolimus: macrolactam isolated from Streptomyces interact with macrophilin 12 (FK binding protein)

22 Calcineurin inhibitors

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24 Contact sensitizers DNCB, DCP and SADBE Immunotherapy of warts, alopecia areata, skin cancers Mechanism: type IV hypersensitivity Cell-mediated response acts against complex of contact agent Alter expression of anti hair follicle epitopes/antibodies for alopecia areata

25 Treatment of warts Clearance rate: 69-91% for DNCB 62-88% for DCP 11-86% for SADBE Mean duration of therapy 7 weeks S/I: eczema, blistering (56%), contact urticaria, vitiligo-like

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29 Other indications DNCB: 80% regression of BCC and SCC and actinic keratosis from total 2000 lesions 32% complete response in 113 tumors Complete clinical response of melanomas DCP: extensive alopecia areata; regrowth of terminal hair 48% Chronic prurigo nodularis, refractory atopic dermatitis

30 Imidazoquinolines Imiquimod and resiquimod Antiviral and antitumor properties Not display direct antiviral and antiproliferative actions but through stimulation of innate immunity

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32 Anti-virus Anti-tumor

33 Anogenital warts Several double-blind, randomized, placebo-controlled trials Largest trial: 311 male and female; 1%,5% imiquimod (apply 3 times/wk) and placebo Total clearance rate with 5% imiquimod and placebo 50% vs 11%, p< Median time for clearance 8 wk for women and 12 wk for men

34 Efficacy of topical imiquimod (IM) in adult patients with anogenital warts. Summary of randomised, double-blind trials Trial Treatment [duration /wk] No. of pts Clearance (% of pts) Complete [time to clearance (wk)] > 50% Recurrence in pts with complete clearance; no of pts (%) Sustain clearanc e rate (%) Arican et al IMI 5% 2x/wk for 8h [12] 33 70[NR] 97 0/23 (0) 70 [24] PLA [NR] 20 1/1 (100) 0 [24] Beutner et al IMI 5% 3x/wk for 24h [8] [4-10] 76 3/16 (19) 29 [10] PLA 50 0 [NA] 8 NA 0 [10] Beutner at al IMI 5% qd for 8h [<16] 94 52[med 9] 93 9/48 (19) 41 [12] IMI 1% qd for 8 h [<16] PLA [med 7] 3 [med 12] /12 (17) 0/3 (0) 11 [12] 3 [12] Edwards et al IMI 5% 3x/wk for 6-10h [<16] [8-12] 76 6/45 (13) 36 [12] IMI 1%3x/wk for 6-10h [<16] [NR] 35 0/18 (0) 21 [12] PLA [NR] 28 1/10 (10) 9 [12]

35 Efficacy of topical imiquimod (IM) in adult patients with anogenital warts. Summary of randomised, double-blind trials Trial Treatment [duration /wk] No. of pts Clearance (% of pts) Complete [time to clearance (wk)] > 50% Recurrence in pts with complete clearance; no of pts (%) Sustain clearanc e rate (%) Nakagawa IMI 5% 3x/wk for 6-10h [<16] 55 (47) 64[med 8] NR NR NR IMI 1% 3x/wk for 6-10 h [<16] 57 (44) 40 [med 8] NR NR NR PLA 53 (47) 34 [med 11] NR NR NR Versus fluorouracil (5-FU) Romero- Sanchez et al IMI 5% 3x/wk [16] 55 (100) 58 [12] NR 1/32 (3) 56 [12] 5-FU 1% 3x/wk [16] 55 (100) 36 [13] NR 0/20 (0) 36 [12]

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37 Efficacy of topical imiquimod (IM) with anogenital warts in HIV patients Trial Treatment No. of pts Clearance (%pts) (duration,wk) Complete Partial Cusini et al IM 3/wk( 16)HIV IM 3/wk( 16)HIV Gilson et al IM 3/wk ( 16) PLA

38 Anogenital warts Clearance rate higher and/or faster in women than men Edwards et al, Nakagawa et al: efficacy independent of gender, baseline wart area, length of time wart appeared Recurrence of warts occurred over <24 wk in 0-19% (5% imiquimod) vs 0-100% (placebo) HPV type and outcome: 132 pts, HPV type by PCR; complete response 76.2% HPV-6, 66.7% HPV-11, 35% HPV-6 plus 11 and 6.3% for unclassified HPV Frequency of application: 5%imiquimod in external genitalia in men: complete clearance 3/wk (35%), 1/day (28%), 2/day (24%), 3/day (27%),P=0.88 but increase local adverse reactions

39 Imiquimod vs ablative Rx in anogenital warts Nonblind trial, 358 pts (71% men) Total clearance Recurrence (%) Sustained efficacy (%) 3 mo 6 mo ITT at 6 mo (%) 5% imiquimod /wk-8 hr-16wk (n=115) Ablative Rx+imiquimod (n=103) Ablative Rx alone (n=100)

40 Efficacy of topical imiquimod (IM) with nongenital warts resistant to previous treatment Trial Treatment No. of pts Complete Mean time (duration,wk) clearance to clearance (%pts) (wk) Grussendorf et al IM bid( 24) Hengge et al IM 5/wk( 16) 50* 30 9 Micali et al IM 5/wk ( 16) 15** 80 3 *1/3 immunocompromised pts **Subungual and periungual warts

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44 *NS Efficacy of topical imiquimod (IM) and placebo (PL) in molluscum contagiosum applied 3/week t children aged 1-9 years Trial Treatment No. of pts Complete clearance (duration,wk) (%pts) 3M study A IM( 16) * PL M study B IM( 16) * PL Theos et al IM(12) 12 33* PL 11 9

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47 Miscellaneous : HSV infection Imiquimod applied 1/wk, 2/wk, 3/wk, placebo; fail to affect the primary efficacy: recurrence in a median of 54, 60, 64, 53 days over 16-wk follow-up Imiquimod 5% not effective in HSV infection

48 Miscellaneous : Keloids Imiquimod applied daily for 8 wk to prevent recurrence of excised earlobe keloids in adult pts (n=11 and 8); recurrence free 75% at 24-wk follow-up Siriraj Hospital: 35 pts, applied daily 2 wk and alternate night 8 wk: recurrent rate 2.9% pinna and 83.3% at chest and neck Imiquimod following tangential shave excision was efficacious in earlobe keloids Imiquimod could effectively prevent recurrence of excised keloids, esp. In the area that had less tension such as pinna

49 Efficacy of topical imiquimod (IM) and placebo (PL) in actinic keratosis applied 2-3/week to 25 cm 2 treatmen areas Trial Treatment No. of pts Clearance (%pts) (duration,wk) Complete >75%reduction Alomar et al IM 3/wk(4/8) ** 66** PL Jorizzo et al IM 3/wk(4/8) ** 61** PL Koman et al IM 3/wk(16) * 64* PL Lebwohl et al IM 2/wk(4/8) * 59* PL Szeimies et al IM 3/wk(16) * 72* PL *p<0.001, **p<0.0001

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54 *P<0.01,**p<0.001, ***p< Efficacy of topical imiquimod (IM) and placebo (PL) in basal cell carcinoma (BCC) Trial Treatment No. of pts Histological clearance (%pts) (duration,wk) Geisse et al IM 3/wk(12) 29 52* IM 5/wk(12) 26 81*** IM qd(12) 31 87*** IM bid(12) ** PL Geisse et al IM 5/wk(6) ** IM qd(6) ** PL Schulze et al IM qd(6) 84 80** PL 82 6 Shumack et al IM 3/wk(12) 20 60** IM 5/wk(12) 23 70** IM qd(12) 21 76* PL superficial BCC nodular BCC

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57 Efficacy of topical imiquimod (IM) and placebo (PL) in lentigo maligna (stage 0 melanoma) Trial Treatment No. of pts Complete clearance (duration,wk) (%pts) Fleming et al IM qd (6) 6 67 Haque et al IM qd (12) Naylor et al IM qd (12) Powell et al IM 3/wk (6) Wolf et al IM qd ( 13) 5 100

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60 5% imiquimod in alopecia universalis, applied once daily for 4 months but alopecia is recurrent

61 Extramammary Paget s disease with 5% imiquimod 3/week for 5 weeks

62 Tolerability Systemic adverse reactions: headache, nausea, anorexia, fatigue, myalgia, infection, lymphadenopathy Local skin reactions: erythema, excoriation, scabbing, erosion, edema, itching, burning, vitiligo-like

63 Topical imiquimod 5% USA Europe External genital and perianal warts in pts aged 12 years Biopsy-confirmed, primary superficial BCC in immunocompetent adults with max tumor of 2 cm on trunk, neck or extremities Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on face or scalp in immunocompetent adults when surgical methods are less appropriate External genital and perianal warts in adults Small superficial BCC in adults Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on face or scalp in immunocompetent adults when cryotherapy or other options are less appropriate

64 Dosage and administration Indication Frequency Duration External 3/wk for 6-10 h Until clearance or Anogenital warts for max. 16 wk Superficial BCC 5/wk for 8 h 6 wk (extra 1 cm (biopsy-confirmed) around BCC) Actinic keratosis 2/wk (US) 16 wk (US) or 4 wk 3/wk (EU) for 8 h followed by 4 wk without Rx and 1 further 4wk cycle if required (EU)

65 Conclusion Topical imiquimod is an effective option for treatment anogenital warts, sbcc and actinic keratosis Overall short-term clearance rate of 40-87% with these lesions Well tolerated and mild systemic reactions Non-invasive method, easy-to-use, self treatment, tissue-sparing and alternative to ablative treatment options

66 THANK YOU