Topical Tazarotene Gel, 0.1%, As a Novel Treatment Approach For
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1 1 PLAN OF THESIS 2 3 4 MICRONEEDLING VERSUS TOPICAL TAZAROTENE 0.1% GEL FOR THE 5 TREATMENT OF ATROPHIC POST ACNE SCARRING - A RANDOMIZED 6 CONTROLLED STUDY 7 8 9 SUBMITTED IN PARTIAL FULFILLMENT OF THE DEGREE 10 11 OF 12 13 MD (DERMATOLOGY, VENEREOLOGY AND LEPROLOGY) 14 15 OF THE 16 17 POST-GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH 18 CHANDIGARH 19 20 BY 21 22 23 DR.AFRA T P 24 25 JUNIOR RESIDENT 26 DEPARTMENT OF DERMATOLOGY, VENEREOLOGY AND LEPROLOGY 27 PGIMER, CHANDIGARH 28 29 30 31 GUIDE: 32 33 DR TARUN NARANG 34 35 ASSISTANT PROFESSOR 36 DEPARTMENT OF DERMATOLOGY, VENEREOLOGY AND LEPROLOGY 37 PGIMER, CHANDIGARH 38 39 40 CO-GUIDE: 41 42 DR SUNIL DOGRA 43 44 ADDITIONALPROFESSOR 45 DEPARTMENT OF DERMATOLOGY, VENEREOLOGY AND LEPROLOGY 46 PGIMER, CHANDIGARH Downloaded From: https://jamanetwork.com/ on 09/23/2021 2 47 48 49 INDEX 50 51 52 Summary of the Proposed Research 3-4 Review of Literature 5-24 Aims and Objectives 25 Materials and Methods 26-33 Statistical analysis 34 Ethical Justification 35 Bibliography 36-42 Annexure I Consent form 43 Annexure II Study Proforma 44-46 Annexure III Patient Information Sheet 47-51 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 Downloaded From: https://jamanetwork.com/ on 09/23/2021 3 68 SUMMARY OF THE PROPOSED RESEARCH 69 70 Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit. It manifests clinically 71 as non-inflammatory (open and closed comedones) or inflammatory (papules, pustules and 72 nodules) lesions. The major brunt of the disease is borne by adolescents aging 16-20 years as 73 shown by a study in India1. Scarring as a sequel to acne can occur in up to 95% of acne patients 74 and 30% may develop cosmetically disfiguring scarring.2 75 Various factors have a role in the causation of acne. The major ones are increased sebum 76 production, hypercornification of pilosebaceous duct, abnormal colonization of pilosebaceous 77 unit by Propionibacterium acnes and inflammation. The uninhibited inflammatory process in 78 acne initiate the process of wound healing with the granulation tissue formation and remodeling 79 of extracellular matrix.3 Depending on the activity and balance between the components 80 involved in the process, there can be a net loss or gain of collagen forming atrophic or 81 hypertrophic scars respectively.4 Thus the inflammatory process associated with acne lead to post 82 acne scarring. 83 Jacob et al classified atrophic acne scars as icepick (60%–70% ), rolling(15%–25%) and boxcar 84 (20%–30%) depending on their shape.5 For the ease of identification and stratification of 85 severity, atrophic acne scars are graded by different scales, of which the most popular ones are 86 the qualitative scale and the quantitative scale proposed by Goodman and Baron.6, 7 87 Eventhough acne scarring is permanent, the appearance can be improved with various medical, 88 laser, surgical and tissue augmentation techniques. Topical retinoids are the mainstay of medical 89 management for macular post acne scars. They reduce epidermal melanin by inhibiting the action 90 of tyrosinase and and also by reduction of melanosome transfer to keratinocytes. Retinoids also 91 normalizes keratinocyte differentiation, reduces the inflammation and stimulates collagen 92 synthesis.8, 9 Topical tazarotene is therapeutically effective as 0.1% gel or 0.1% cream.10, 93 11Tazarotene (0.1%) gel was found to be superior to adapalene (0.1%) and tretinoin (0.025%, 12 94 0.1%) for the treatment of acne vulgaris. Based on its mechanism of action and role in collagen Downloaded From: https://jamanetwork.com/ on 09/23/2021 4 95 synthesis, topical tazarotene is a logical choice to investigate for the management of atrophic 96 post acne scars. 97 Among the procedural methods, microneedling with dermaroller is a novel and promising 98 option. It is a minimally invasive procedure for the management of atrophic acne scars.13 It 99 causes per-cutaneous collagen induction by augmenting the natural process of wound healing.14 100 There are studies establishing the efficacy of newer dermatosurgical technique, the 101 microneedling in atrophic post acne scar management.15, 16 The efficacy of topical tazarotene in 102 the management of acne vulgaris and reducing PIH has been proved in previous published 103 studies.12, 17This is a pilot study comparing microneedling and topical tazarotene for the 104 treatment of atrophic post acne scarring in regard to extent and rapidity of improvement, patient 105 satisfaction and any adverse events if any. 106 107 108 109 110 111 112 113 114 115 116 117 118 119 Downloaded From: https://jamanetwork.com/ on 09/23/2021 5 120 121 Introduction 122 Acne vulgaris is one of the most common dermatoses in the world. It is a chronic inflammatory 123 disease of the pilosebaceous unit. Majority of the incidence of acne is seen in adolescence. Acne 124 occurs over the seborrheic areas like face and trunk. It may manifest clinically as non 125 inflammatory (open and closed comedones) or inflammatory (papules, pustules and nodules) 126 lesions. The inflammatory process associated with acne may lead to post acne scarring and is 127 common sequelae. Scarring occurs due to gain or loss of collagen with resultant formation of 128 hypertrophic or atrophic scarring respectively. Scarring is a distressing phenomenon and is most 129 unwelcome when it occurs on the face. Severe scarring on the face is physically disfiguring and 130 causes significant psychological distress. The affected individual may suffer from lack of self 131 confidence, low self-esteem and many other psychological ill effects. Even though post acne 132 facial scarring is a challenging problem to manage there are various methods to improve the 133 appearance of scar. 134 Epidemiology 135 Acne is an almost universal condition in younger people. Acne usually starts in the early teens 136 near puberty with the onset of facial sebum production and facial comedones followed by 137 inflammatory lesions. Acne lesions usually develop earlier in females as puberty occurs earlier in 138 them. The major brunt of the disease is borne by the age group 16-20 years as shown by a study 139 in India.1 Mean age of onset was 15.97 years, affecting males more than females. Prevalence of 140 acne in age group of 12-17 years is 50-60% in boys and 38-73% in girls by a study in India.1 141 Scarring as a sequel to acne can occur in up to 95% of acne patients and 30% may develop 142 cosmetically disfiguring scarring.2 143 Pathogenesis 144 Pathogenesis of Acne 145 Acne is a multifactorial disease. The four basic factors which have been identified include: (i) 146 sebaceous gland hyperactivity and seborrhea (ii) abnormal follicular differentiation and Downloaded From: https://jamanetwork.com/ on 09/23/2021 6 147 hyperkeratinization of the pilosebaceous duct, (iii) abnormal colonization of the pilosebaceous 148 duct with microbial flora especially P. acnes and (iv) increased inflammation. 149 1. Sebaceous gland hyperactivity and seborrhea: 150 Increased production of sebum by sebaceous glands leads to development of acne.18 151 Triglycerides and lipoperoxides in sebum have an active role in acne formation. Free fatty acids 152 formed by the breakdown of triglycerides promote colonization of P.acnes, cause inflammation 153 and is comedogenic.19 Lipoperoxides produce proinflammatory cytokines and stimulate the 154 peroxisome proliferator-activated receptor (PPAR) pathway, increasing sebum production.20 155 Androgenic hormones such as testosterone and more active DHT also have a significant role in 156 acne pathogenesis. These hormones act on the sebocytes and regulate their proliferation and 157 differentiation.21 Corticotropin releasing hormone also has a role and it is seen that corticotropin 158 releasing hormone receptors are increased in the sebocytes of patients with acne.22 159 2. Comedogenesis : 160 Follicular epidermis including that of the infundibulum becomes hyperproliferative and the 161 corneocytes become increasingly cohesive with the formation of a plug in the follicular ostium. 162 The plug so formed further causes collection of keratin, sebum and bacteria in the follicle and 163 dilation of the upper hair follicle producing a microcomedone. 164 Keratinocyte hyperproliferation is stimulated by DHT, subnormal levels of linoleic acid, 165 increased interleukin 1 alpha (IL-1) activity and effects of P.acnes.23, 24 Fibroblast growth factor 166 receptor (FGFR)- 2 pathway also causes proliferation of corneocytes and is androgen 167 dependent.25 168 Ductal hyperkeratinisation is seen histologically as microcomedones and clinically as 169 blackheads, whiteheads and other forms of comedones such as macrocomedones .The number 170 and size of follicular casts (micro-comedones) correlates with acne severity.26 171 3. Colonization of Intrafollicular duct with P.acnes : 172 P.acnes is a Gram-positive, anaerobic, and microaerobic bacterium found in the pilosebaceous 173 follicle. Colonization of intrafollicular duct with P.acnes has significant role in comedogenesis 174 and initiating inflammation. The breakdown of triglycerides into free fatty acids by P.acnes Downloaded From: https://jamanetwork.com/ on 09/23/2021 7 175 further promotes its colonization resulting in comedogenesis .19The carbohydrate antigen present 176 in the cell wall of P.acnes causes antibody development whose titres correlates with severity of 177 acne.27 178 4. Inflammation: 179 The microcomedone formed by follicular plugging further expand by accumulation