Topical immunomodulation

Charoen Choonhakarn,MDDivision of DermatologyKhon Kaen University

Vitiligo

Atopic dermatitis

Seborrheic dermatitis

Oral lichen planus

Anogenital warts

Bowen’s disease actinic keratosis

Malignant melanoma

Basal cell carcinoma

Side effects

Topical immunotherapy

Immune response modifier

Immunomodulator

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)

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

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

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

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

• 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)

Toll-like receptor (TLR)

Toll-like receptor (TLR)

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)

Calcineurin inhibitors

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

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

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

Imidazoquinolines• Imiquimod and resiquimod• Antiviral and antitumor properties• Not display direct antiviral and

antiproliferative actions but through stimulation of innate immunity

Anti-tumor

Anti-virus

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

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)

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]

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

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

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)

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

Bowenoid papulosis

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

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

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

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

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

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

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

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

Tolerability

• Systemic adverse reactions:headache, nausea, anorexia, fatigue, myalgia, infection, lymphadenopathy

• Local skin reactions:erythema, excoriation, scabbing, erosion, edema, itching, burning, vitiligo-like

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

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)

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

THANK YOU