topical immunomodulation - kku web hosting 17/jalurn... · anogenital warts • clearance rate...
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Topical immunomodulation
Charoen Choonhakarn,MDDivision of DermatologyKhon Kaen University
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Vitiligo
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Atopic dermatitis
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Seborrheic dermatitis
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Oral lichen planus
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Anogenital warts
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Bowen’s disease actinic keratosis
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Malignant melanoma
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Basal cell carcinoma
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Side effects
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Topical immunotherapy
Immune response modifier
Immunomodulator
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Immune system-Innate immune systemphagocytic cells to recognized pathogen
natural killer cells (NK)
-Adaptive or acquired immune systemrecognition of foreign Ag by major histocompatibility complex (MHC) I,II and by Ag-presenting cell (Langerhans’ cells)
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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
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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 agentsTopical corticosteroids Calcineurin inhibitors: macrolactam Tacrolimus 0.03%,0.1%
Pimecrolimus 1%
Mycophenolate mofetil
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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
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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
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• 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 humoralimmunity (IL-4,5,6,9,10,13)
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Toll-like receptor (TLR)
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Toll-like receptor (TLR)
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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 macrophilin12 (FK binding protein)
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Calcineurin inhibitors
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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
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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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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
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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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Anti-tumor
Anti-virus
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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<0.0001
• Median time for clearance 8 wk for women and 12 wk for men
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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 (%)
Sustainclearance rate (%)
Arican et al IMI 5% 2x/wk for 8h [12] PLA
33
10
70[NR]
10 [NR]
97
20Beutner et al IMI 5% 3x/wk for
24h [8] PLA
45
50
40 [4-10]
0 [NA]
76
8
3/16 (19)
NA
29 [10]
0 [10]Beutner at al IMI 5% qd for 8h
[<16]IMI 1% qd for 8 h [<16]PLA
94
90 95
52[med 9]
14[med 7]3 [med 12]
93
4123
9/48 (19)
2/12 (17)0/3 (0)
41 [12]
11 [12]3 [12]
Edwards et al IMI 5% 3x/wk for 6-10h [<16]IMI 1%3x/wk for 6-10h [<16]PLA
109
102
100
50 [8-12]
21 [NR]
11 [NR]
76
35
28
6/45 (13)
0/18 (0)
1/10 (10)
36 [12]
21 [12]
9 [12]
70 [24]
0 [24]
0/23 (0)
1/1 (100)
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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 (%)
Sustainclearance rate (%)
Nakagawa IMI 5% 3x/wk for 6-10h [<16] IMI 1% 3x/wk for 6-10 h [<16]PLA
55 (47)
57 (44)
53 (47)
64[med 8]
40 [med 8]
34 [med 11]
NR
NR
NR
NR
NR
NR
NR
NR
NR
Versus fluorouracil
Romero-Sanchez et al
(5-FU)
IMI 5% 3x/wk [16]
5-FU 1% 3x/wk [16]
55 (100)
55 (100)
58 [12]
36 [13]
NR
NR
1/32 (3)
0/20 (0)
56 [12]
36 [12]
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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+ 75 31 24
IM 3/wk(≤16)HIV- 50 62 24
Gilson et al IM 3/wk (≤16) 65 11 38
PLA 35 6 14
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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
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Imiquimod vs ablative Rx in anogenital wartsNonblind trial, 358 pts (71% men)
Total clearance Recurrence (%) Sustained efficacy
(%) 3 mo 6 mo ITT at 6 mo (%)
5% imiquimod 65 6 6 64
3/wk-8 hr-16wk
(n=115)
Ablative Rx+imiquimod 73 8 8 57
(n=103)
Ablative Rx alone 92 16 26 63
(n=100)
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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) 37 27 19
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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Bowenoid papulosis
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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) 217 24*
PL 106 26
3M study B IM(≤16) 253 24*
PL 126 28
Theos et al IM(12) 12 33*
PL 11 9
*NS
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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
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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
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Efficacy of topical imiquimod (IM) and placebo (PL) in actinic keratosis applied 2-3/week to 25 cm2 treatmen areas
Trial Treatment No. of pts Clearance (%pts)
(duration,wk) Complete >75%reduction
Alomar et al IM 3/wk(4/8) 129 55** 66**
PL 130 2 4
Jorizzo et al IM 3/wk(4/8) 123 54** 61**
PL 123 15 25
Koman et al IM 3/wk(16) 242 48* 64*
PL 250 7 14
Lebwohl et al IM 2/wk(4/8) 215 45* 59*
PL 221 3 12
Szeimies et al IM 3/wk(16) 147 57* 72*
PL 139 2 4
*p<0.001, **p<0.0001
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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* superficial BCCIM 5/wk(12) 26 81***
IM qd(12) 31 87***
IM bid(12) 10 100**
PL 32 19
Geisse et al IM 5/wk(6) 185 82**
IM qd(6) 179 79**
PL 360 3
Schulze et al IM qd(6) 84 80**
PL 82 6
Shumack et al IM 3/wk(12) 20 60** nodular BCCIM 5/wk(12) 23 70**
IM qd(12) 21 76*
PL 24 13
*P<0.01,**p<0.001, ***p<0.0001
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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) 21 90
Naylor et al IM qd (12) 28 93
Powell et al IM 3/wk (6) 12 83
Wolf et al IM qd (≤ 13) 5 100
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5% imiquimod in alopecia universalis, applied once daily for 4 months but alopecia is recurrent
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Extramammary Paget’s disease with 5% imiquimod 3/week for 5 weeks
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Tolerability
• Systemic adverse reactions:headache, nausea, anorexia, fatigue, myalgia, infection, lymphadenopathy
• Local skin reactions:erythema, excoriation, scabbing, erosion, edema, itching, burning, vitiligo-like
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Topical imiquimod 5%USA
• 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 actinickeratosis on face or scalp in immunocompetent adults when surgical methods are less appropriate
Europe
• External genital and perianal warts in adults
• Small superficial BCC in adults
• Clinically typical, nonhyperkeratotic, nonhypertrophic actinickeratosis on face or scalp in immunocompetent adults when cryotherapy or other options are less appropriate
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Dosage and administrationIndication 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)
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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
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THANK YOU