Keloid and hypertrophic scars management. Demographics Young, 10-30 years - more prone to trauma - more elastic fiber - greater rate of collagen synthesis.

Keloid and hypertrophic scars management

Demographics

• Young, 10-30 years - more prone to trauma - more elastic fiber - greater rate of collagen synthesis

• Darker skin - incidence 4.5-16%

Pathogenesis of abnormal wound healing

Imbalance of deposition and degradation of ECM protein

Clinical manifestation

Dermatol Surg 2014;40:825–831

Treatment response1. Scar location

• No general agreement regarding the association between the scar location and treatment outcome.

• Nouri et al. : facial, shoulder, and arm scars responded better than the anterior chest wall.

• Dierickx et al. : better response for facial scars. • Alster and Nanni :found no relation between

scar location and response to treatment

2.Scar duration

• Some authors have reported that scars <1 year old respond better than older scars

• Others have not found such an association

MANAGEMENT

INTRALESIONAL AND TOPICAL

Corticosteroid

Mechanism• Inhibit fibroblast growth• Promoting collagen degradation• Inhibit TGF-B1• Induce apoptosis in fibroblast• Inhibit a-2-macroglobulinactive collagenase Side effects• pain, atrophy, changes in pigmentation, cushing’s

syndrome

Corticosteroid

• Triamcinolone acetonide : MC used - Topical : superficial lesions - injection : Concentration = 10-40 mg/ml• Depth : mid-dermis• Interval : 3-4 weeks• Minimized pain : - local/topical anesthesia• If after 4 injection sessions, the keloid has not begun

to regress or get softer, surgery is recommended.

Corticosteroid• Triamcinolone injection alone is effective in reducing the

volume of lesions in a majority of patients ( level A)• soften and flatten keloids• cannot narrow hypertrophic scars or eliminate keloids

Combination• 5-FU + triamcinolone seems to be superior to IL steroid therapy

alone - reduction size : 92% vs 73%• Postoperative IL triamcinolone after surgical excision seems to

prevent recurrence ( level B)

5-FU

Mechanism• Pyrimidine analog, inhibit DNA & RNA • Interfere fibroblast proliferation• Induce fibroblast apoptosis without necrosis• Inhibit TGF-B signaling in collagen I production Side effects• pain, hyperpigmentation, tissue sloughing,

purpura

5-FU• 5-FU alone is effective in the treatment of keloids (level B)

Combination• 5-FU + surgical excision of keloids - prevents recurrence after excision in majority of patients• 5-FU + triamcinolone - superior over triamcinolone alone ( level B) - less painful, skin atrophy and telangiectasia than

triamcinolone alone (level C)• Dose :0.1 ml of KA(10mg/ml) + 0.9 ml of 5-FU(50mg/ml)

5-FU

Combination• 5-FU : suppress fibroblast activities• Steroid : suppress inflammation and fibroblast• PD: suppress angiogenesis

- 5-FU/TAC/PDL > 5-FU/TAC > 5-FU alone

-5-FU/TAC/PDL = 5-FU/TAC > TAC alone

Bleomycin Mechanism• Inhibit synthesis of DNA• Inhibit lysyl oxidase ( cross-link collagen enz.)• Antitumor, antiviral and antibacterial

Side effect• Hyperpigmentation, dermal atrophy, ulcer• Systemic SE are not concern because the concentration

and dosage are not sufficient to incite systemic problems.• More expensive

Bleomycin

Technique• Multiple injection• Multiple punctures using a 22-gauge needle ( tattoo technique)

Bleomycin

• IL bleomycin is effective - improve cosmetic appearance - relieves pruritus and pain• ¾ of the patients showing good to excellent

results (level B)• Further studies are need before included in

future treatment protocol.

Interferons

Mechanism• All interferon isoforms ( a , b , g ) - reduce collagen and ECM production - increasing collagenase level - inhibit TFG-B1 Side effects• flu-like (fever, chills, night sweats, fatigue,

myalgia, and headache)

Interferon a-2b Pro.• IL IFN a-2b (1.5 mIU, twice daily for four days) - 50% in keloid size after only 9 days - more effective than IL steroid Con.• Davison and colleagues - IFN- a 2b to be less effective than IL triamcinolone and terminated

their study early because of rapid and frequent recurrences• There is also conflicting data regarding the efficacy.• Current evidence : not recommend the routine use. It may be used in selected cases.

Interferons

Combination• IFN-a-2b + triamcinolone has been reported to

be superior to triamcinolone alone in reducing the depth and volume of keloids (level C)

Verapamil

Mechanism• Increasing collagenase• Reduce ECM production• Inhibit IL-6, VEGF, TGF-B1• Inhibit fibroblasts proliferation and induce

fibroblast apoptosis

Verapamil

• Lawrence found that excision of keloids followed by pressure dressings and IL verapamil resulted in 55% reduction of keloids.

• D’Andrea et al. found that adjuvant verapamil helped to reduce the incidence of keloid recurrent after surgical excision and topical silicone application

• Limit clinical data showing its efficacy in keloids (level C)

Imiquimod

Mechanism• Stimulates interferon-a increases collagen

breakdown• Alters the expression of apoptosis-associated

genes

Imiquimod

• Used in conjunction with surgical excision - preventing recurrence after surgical excision.• 5% cream effective in prevention of earlobe keloid

recurrent after excision• High rate recurrent at trunk keloid after excision

and 8 week imiquimod treatment.• There are conflicting data about its efficacy.• Antifibrotic effect seems to be short-lived and

lesions recur after discontinuation of keloids.

Mitomycin C

Mechanism• Suppress fibroblasts and decrease fibroblast

density

Mitomycin C

• Success with short-term mitomycin C contact immediately after keloid or hypertrophic scar excision

• Seo and Sung found worsening of the lesions and ulcer development.

• Not improve in keloid recurrent rates.• Limit available data. Mostly small,uncontrolled

studies and clinical experience.

TNF-a

Mechanism• Decrease collagen production in keloid fibroblast• mutations in the 1573 fragment of the TNF

receptor II gene have been discovered in some keloids, indicating a role in pathogenesis

• Comparing IL TNF-a vs triamcinolone - triamcinolone was more efficacious in overall

scar improvement ( not statistically sig.)

Silicone products

Mechanism• Not due to pressure• Occlusion and hydration of the stratum corneum with

subsequent cytokine-mediated signaling from keratinocytes to dermal fibroblasts (level C)

• It is also believed that hydration decreases capillary permeability, inflammatory and mitogenic mediators, and collagen synthesis.

• Flattening and softening of scar• Easy of administration, noninvasive

Silicone gel sheet

• Good evidence of efficacy• Standard practice among plastic

surgeons.• SE : skin reaction to the tape,

excessive sweating, difficulty in its application, visibility

Silicone gel

• Does not require fixation.• Nearly invisible when dry• Useful in visible areasProblem• Multiple applications in a day• Wait long enough for drying• Friction by clothes ->early

removal

Silicone products

• Application of silicone gel sheets should begin as soon as reepithelialization is finished

• Silicone gel sheet at least 12 hours/D (12-24) • Silicone gel twice daily• for a minimum of 2 months (6-12 months).

Silicone

• Karagoz et al. found no statistically significant difference between silicone gel and silicone gel sheet

Onion extract ( Allium cepa)

Mechanism• Anti-inflammatory, bacteriostatic, and

collagen down-regulatory properties (increase MMP-1)

• Improves collagen organization in a rabbit ear model

Onion extract ( Allium cepa)• Improve in scar symptoms, appearance or both

observed in multiple RCTs.• Not more efficacious than a petrolatum emollient in

head-to-head comparison.• Mixed results in hypertrophic scars and keloids• Not as effective as either silicone gel or sheet• Combination with traditional therapies believed to

enhance therapeutic efficacy versus either silicone gel sheet or IL steroid alone

• Limited evidence of its efficacy (level C)

Onion extract ( Allium cepa)

Active ingredient: Allium cepa 12%Active Ingredient. Allium cepa 12% plus Vitamin E acetate.

Others therapies

Topical zinc, tretinoin, cyclosporin• Mixed result

Semin Cutan Med Surg. 2009 v.28(2) p.71-6

SYSTEMIC

Others therapies

Relaxin• Growth factor that can stimulate collagenase• Several trial for treatment scleroderma

D-penicillamine• Interfere cross-linking ability of collagen• May be useful in keloid

PHYSICAL THERAPY

Pressure therapy

Mechanism• Decrease in blood flow• Decrease in a2-macroglobulin increase in collagenase• Hypoxia leading to fibroblast degeneration and collagen

degradation• lower levels of chondroitin 4-sulfate, with a subsequent

increase in collagen degradation• reduced mast cell reduced pruritus• Accelerate the remodeling phase

Pressure garment• Pressure therapy should be started

immediately after reepithelialization of the wound

• Should wear these pressure devices for continuous 8 to 24 hours a day for the first 6 months of scar healing.

• 20-40 mmHg for 24 hours a day (amount of effective pressure is

unknown)• SE : discomfort from heat and sweating,

swelling of limbs, rashes, eczema, friction, poor compliance

Pressure therapy

• Pressure therapy alone is considered effective for prevention of hypertrophic burn scars (level C)

• Controversial evidence-based data about their value in reducing the prevalence or magnitude of scarring.

Pressure therapy

Recommendations• Deep dermal wounds that have healed

spontaneously over weeks• Wounds in children and young adults• Wound in dark skin• Wound in body locations where compression

can be applied

Pressure clips

• Pressure clips are in common use for patients with earlobe keloid.

RADIATION

Radiotherapy

Mechanism• Inducing apoptosis of fibroblast proliferation

• SE: hyperpigmentation, risk of radiation-induced malignancy,

• Contraindicated : children, areas of high carcinogenic potential (breast and thyroid)

Radiotherapy• Radiation therapy alone not shown much success except in

large doses.• Post-excision radiation therapy as an adjunct to surgical

excision - effective approach for the management of extensive HTS

and keloids which causes significant morbidity/limitation of movement/contracture.

• Recurrence rate varying from 9 to 72% (LEVEL B)• Effective Dose of 30-40 Gy seems to be sufficient to prevent

recurrences of keloid after surgical excision (LEVEL B)

Radiotherapy• risk of carcinogenesis• few reports in the literature of malignancies arising from the

treatment of keloid scars with radiotherapy

• AE: skin redness, skin peeling, telangiectasia and permanent skin color changes, generally hypopigmentation (LEVEL B)

• effective option for recalcitrant and large keloids not responding to other treatments in centers where facilities are available, particularly, in combination with surgical excision

Radiation

• Radiation, intralesional steroid and 5-FU prevent recurrence more efficiently than topical imiquimod and interferons (LEVEL B)

SURGERY

Surgical excision

• I/C : scar contracture esp. joint loss of function

• after excision of keloid, an adjuvant should always be used (LEVEL A)

• Recurrence 50-100%, exception is earlobe keloid which recurs much less frequently (LEVEL B)

Surgical excisionAdjuvant tiamcinolone, postoperative site q 2-3 weeks*4 - begin 1 week after suture removal - The steroid slows wound healing; therefore, sutures should remain in place for 10 to 20 days.pressure garments combined with class 1 topical steroid - begin 1 week after suture removalsilicone gel sheetCurad scar therapy(Polyurethane) - silicone-free adhesive, left on for 12+ hours/day for as long as the

keloid become flatter and then applied weekly to prevent recurrent - three key ingredients includes: Omega-6 (Safflower Oil), Retinyl

Palmitate (Vitamin A) and Tocopherol (Vitamin E) Acetate.

Surgical excision

Adjuvant -IFN alpha-2B : immidiate after surgery& 1-2 wk

laters -5-FU -Bleomycin -imiquimod immediate after surgery and daily for 8

weeks -topical tacrolimus -pentoxyfylline 400 mg tid , limit success

Surgical excision

Adjuvant- MTX 15-20 mg. single dose q 4 day, starting a week

after surgery and continuing for 3-4 months - colchicine : inhibit collagen synthesis, collagenase

sitmulation - collagenase : IL ineffective - superpotent class I steroid : apply daily or BID - Antihistamine : used for pruritus - sitng stop : herbal, apply 3-4 times/day

Surgical excision• narrow base keloid - simple elliptic excision,

undermine the base, then close with sutures.

• large bases keloid or large nonpedunculated earlobe keloids

- tongue-like flap.• One should wait 10 to 20

days to remove sutures, especially after earlobe keloid excision.

Tongue-like flap

Cryosurgery• Mild edema and cellular breakdown of the keloid causing a

decrease in the density of fibrous tissue so that the injection can be given easily and uniform dispersal of the drug.

• Monotherapy : 2 courses of 15-20 second freeze-thaw cycles q 3 week

• SE: pain, blistering, edema, temporary hypopigmentation, delayed healing and infection

• To decrease mobidity, the patient should take 2 adult aspirin 1 hour before treatment and apply clobetasol propionate 0.05% ointment tid x 2 days after cryosurgery

Cryosurgery

• Efficacy : 20% - >75% in scar volume reduction• Total/partial success in almost 2/3 - 3/4 of

keloids after at least 3 sessions (LEVEL B)• Combination of LN2 and IL steroids seems to

have a synergistic effect over LN2 alone (LEVEL B)

LASER

Lasers

PDL• Vascular proliferation plays a key role in keloid and

hypertrophic scar• PDL absorbed by Hb coagulation necrosis• Hypoperfusion & hypoxia neocollagenesis collagen fiber heating with dissociation of disulfide bonds

and subsequent collagen fiber realignment release of histamine or other factors that influence fibroblast

activity• Decrease fibroblast proliferation & col3 deposit• Down regulation TGF-B1, increase MMP-13

International journal of dermatology 2007,46, 80-88.

Mechanisms


PDL

• Keloid : more dense and hyalinized collagen bundles form avascular accumulation of coarse collagen bulk

• Theoretical : 585 nm. PDL more limited efficacy in keloid > hypertrophic scar


PDL

• Fluence : - low-fluence PDL : increase procollagen

production - high-fluence PDL : may cause focal dermal

coagulation, greater risk of SE - suggest fluence : 3.5-7.5 J/cm2 , 0.45 ms

PDL

• reduction of scar erythema, height, symptoms, and rigidity.

• Fluences: 6.0 to 7.5 J/cm2 (5 or 7 mm spot size) : 4.5 to 5.5 J/cm2 (10 mm spot size) • pulse durations : 0.45 to 1.5 ms • repeated at 6–8 week time interval

International Journal of Dermatology 2014, 53, 922–936

PDL

• histology - decrease in the number of fibroblasts - collagen fibers appeared looser and less

coarse. Combination• IL corticosteroids decreased pruritus;

however, it did not significantly enhance the clinical outcome.


532 nm, frequency-doubled, Nd:YAG

• This WL is close to 542 nm oxyHb peak• A good choice for keloid & hypertrophic scar

• 532 nm favorable result in treatment pigmented hypertrophic scar compare with 585 nm PDL


Nd:YAG 1064 nm

• Suppress collagen production in fibroblast culture.


Er:YAG laser

• 2940 nm , high water absorption, almost total absorption by the epidermis.

• effectively used to revise hypertrophic, depressed, and burn scars with the greatest improvement in depressed scars.

• Settings: 500–1200 mJ/pulse and 3.5–9 W with a 2 mm handpiece.


carbon dioxide (10,600 nm)

• Mechanism : stimulate release bFGF, inhibit TGF-B1

• Not satisfactory, recurrent rate 39-92%

CO2 combination

• CO2 + Erbium-YAG - In vitro study, increase bFGF, decrease TGF-B1

• Co2 + PDL

carbon dioxide (10,600 nm)

• split-scar study , post surgical scar• compared fractionated CO laser VS diamond

fraise dermabrasion • trend toward less erythema at one month

with fractionated CO2


Argon (488 nm)

• Similar to CO2 laser• Induced excessive localized heat collagen

shrinkage• High recurrent rate : 45-93%

Adjunctive therapy with laser• IL corticosteroids (10–20 mg) with PDL - a recent study did not improve the clinical outcome

significantly, but was effective in decreasing pruritus. - It was suggested that higher corticosteroid concentrations

could have potentially yielded better results, but would also have increased the risk of unwanted side-effects, such as skin atrophy and telangiectasias.

• Hydroquinones, by reducing epidermal pigmentation, may be useful in improving the clinical outcome.

FUTURE DIRECTION

Hydroquinone

• The rational is the albino patients do not develop keloid and vitiligo often causes the underlying keloid to regress.

• Hydroquinone works best if used withing the first 5 months of keloid formation

• Treat excision site plus 1-2 cm. margin


Glucose-6-phosphate dehydrogenase deficiency

• African-American patient have a greater incidence of G6PD deficiency

• Keloids have a greater incidence in African-american patient

• An agent to lower or block G6PD might be successful in treating keloid


Hyperbaric oxygen

• Low oxygen tension (hypoxia) stimulates fibroblasts.

• High oxygen tension may do the opposite.


Botulinum toxin A

• Immobilized the muscle and reduced skin tension by muscle pull, decreasing microtrauma, and inflammation

• Minimized scar tension• Improve erythema, pruritus, and pliability of

these lesions

Arch Plast Surg. 2014 v.41(6) p.620-9

Botulinum toxin A

• In 2006, Gassner et al. demonstrated that BTX injections into the musculature adjacent to the wound (15 IU of BTX-A,Allergan) resulted in enhanced wound healing and less noticeable scars.


Botulinum toxin A

• prospective, uncontrolled study to evaluate the effects of BTA in the treatment of ear keloids with a 24-gauge needle .

• Per session, 70–140 IUs of BTX-A were injected intralesionally into 12 ear keloids in three sessions once a month.

• The results were excellent in three patients, good in five patients, and fair in four patients after 1 year of follow-up. Arch Plast Surg. 2014 v.41(6) p.620-9

Botulinum toxin A

• In a 2009 study by Xiao et al. [69], singledose treatments with BTX-A at 2.5 IU/cm3 of lesion at 1-month intervals (not exceeding 100 IU per patient) were used in 19 patients.

• At six months post-treatment, all patients reported decreases in erythema, itching sensations, and pliability.


Pentoxifylline

• Improve elasticity of hypertrophic scar when injected intradermally

minocycline

• IL minocycline reduced hypertrophy by 85%

Avotermin (TGF-B3)

• TGF-b3 found in higher concentrations during early fetal gestation, is thought to promote scarfree healing by counteracting TGF- b1 and thus reducing excess fibrosis, inflammation, and excess collagen deposition

Mannose-6-phosphate

• inhibitor of TGF- B1and TGF- B2

Human recombinant IL-10(Prevascar)

• Anti-inflammatory and anti-fibrotic cytokines• The absence of IL-10 leads to an amplified inflammatory

response and abnormal collagen deposition.• An adult murine model of wound healing revealed that

injection of IL-10 48 hours before wounding led to decreased inflammation and decreased expression of proinflammatory mediators compared to controls .

• At 3 weeks, the treated wounds showed decreased inflammation, normal dermal architecture, and no abnormal collagen deposition.

CONCLUSION


High risk:History of keloid or HSSurgery at risk region eg. Breast, thorax

Hypoallergenic paper tape : recommended in 2002 guideline for prevention of HS after sx in low risk patient on the basic of advisory board consensus rather than controlled clinical trial data.



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Keloid and hypertrophic scars management. Demographics Young, 10-30 years - more prone to trauma - more elastic fiber - greater rate of collagen synthesis.

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