Evaluating the tolerability and efficacy of etanercept compared to triamcinolone acetonide for the intralesional treatment of keloids

Journal of Drugs in Dermatology, August, 2008 by Brian Berman, Jitendrakumar K. Patel, Oliver A. Perez, Martha H. Viera, Sadegh Amini, Samantha Block, Deborah Zell, Sujatha Tadicherla, Adriana Villa, Claudia Ramirez, Tami De Araujo

ABSTRACT: Background: Tumor necrosis factor-alpha (TNF-[alpha]) is a proinflammatory and profibrotic cytokine that inhibits degradation of collagen and glycosaminoglycans. Etanercept, a recombinant TNF-[alpha] receptor fusion protein, may decrease excessive fibrous tissue in keloids.

Objective: To evaluate the tolerability and efficacy of etanercept as compared to triamcinolone acetonide (TAC) for the treatment of keloids.

Methods: Twenty subjects were randomly assigned to receive monthly intralesional injections of either 25 mg of etanercept or 20 mg of TAC for 2 months. Keloids were evaluated at baseline, week 4, and week 8 by subjects and investigators in a blinded fashion using physical, clinical, and cosmetic parameters. Photographs were taken and adverse events were noted during each evaluation.

Results: Etanercept improved 5/12 parameters including significant pruritus reduction, while TAC improved 11/12 parameters at week 8, although no statistical difference was observed as compared to baseline. There was no significant difference between the 2 treatment groups. Both treatments were safe and well tolerated.

Conclusion: Etanercept was safe, well tolerated, improved several keloid parameters, and reduced pruritus to a greater degree than TAC therapy. However, further studies are required before it can be recommended for the treatment of keloids.

INTRODUCTION

Injury to the skin induces the activation of the normal healing process, which consists of overlapping inflammatory, proliferative, and maturation phases. During the inflammatory phase, proinflammatory cytokines are released, including interleukin (IL)-1 and IL-6, transforming growth factor-beta (TGF-[beta]) types 1 and 2, and tumor necrosis factor-alpha (TNF-[alpha]), among others. The proliferative phase involves collagen deposition, granulation tissue formation, epithelialization, wound contraction, and fibroblast growth with extracellular matrix (ECM) formation that includes collagen and fibronectin.

In certain individuals, this normal physiologic healing process becomes uninhibited and may cause an extension of collagen beyond the margins of the wound resulting in skin quality alterations, loss of functionality, scarring, and keloid formation. (1-8) Almost any skin injury may result in keloid formation, including ear piercings, lacerations, abrasions, tattooing, vaccinations, injections, insect bites, and burns. (5,8), (9) The incidence of keloid formation has been estimated to be up to 16% in darker skinned and Hispanic individuals, and is higher in genetically predisposed persons and individuals between 10 and 30 years of age. (2), (3), (5), (6), (8), (10-12)

There are numerous therapeutic methods used in the management of keloids; however, no specific treatment has been found to be 100% safe and effective. Current treatments include intralesional corticosteroids, interferon-alpha (IFN-[alpha]) and IFN-[alpha]2b, belomycin, fluorouracil (FU), topical calcineurin inhibitors, and imiquimod. Surgical therapies include excision, tangential shaving, cryosurgery, radiotherapy, and lasers, followed by the application of pressure with ligatures and silicone gel-sheeting. Newer modalities include ultraviolet-A (UVA), verapamil, retinoids, TGF-[beta], IL-10, intense pulsed light (IPL), photodynamic therapy (PDT), querecetin (a flavonol), prostaglandin E2, and gene therapy. (2), (3), (5), (8-10), (12-14) Monocyte/macrophage-derived TNF-[alpha] plays a critical role in the development of inflammatory, infectious, and autoimmune diseases. At low concentrations, it inhibits collagen phagocytic pathways in fibroblasts, prevents degradation of collagen and glycosaminoglycans, stimulates the synthesis of matrix metalloproteinases (MMPs) and prostaglandin E2, and increases collagen activity, thus acting as a profibrotic agent. (14), (15), (16) However, at higher concentrations, TNF-[alpha] may stimulate collagenases and decrease collagen synthesis. (4) (17) Etanercept is a recombinant TNF-[alpha] receptor fusion protein composed of the extracellular ligand-binding part of the human p75 connected to the Fc portion of human immunoglobulin G1 (lgG1), and is capable of binding to and neutralizing the activity of TNF-[alpha]. (16) Etanercept is approved by the Food and Drug Administration (FDA) for the treatment of psoriatic arthritis, polyarticular juvenile rheumatoid arthritis (JRA), rheumatoid arthritis, chronic plaque psoriasis, and ankylosing spondylitis. (16) Under that premise, a study was designed to assess the ability of intralesional etanercept to treat keloids by the inhibition of TNF-[alpha] and its profibrotic action. The objective of this study was to evaluate the tolerability and efficacy of the treatment of keloids with intralesional etanercept as compared with intralesional triamcinolone acetonide (TAC).

METHODS

In this single-center, prospective, randomized, investigator-blind, comparative, IRB-approved study, 20 subjects, 18 years of age or older and nonreactive to purified protein derivative (PPD), were assigned to received 25 mg/mL intralesional etanercept (n = 10) or 20 mg/mL intralesional TAC (n = 10) at baseline and week 4. Subjects' keloids must have been present for at least 1 year, and been less than or equal to 2 cm in size with no more than 1 episode of recurrence. Exclusion criteria included individuals who were pregnant or nursing, or had uncontrolled diabetes mellitus, a history of recent infections, immunosuppression, prior application of etanercept on the study keloid, or treatment to the study keloid 6 weeks prior to the study. Patients with a history of central nervous system complications, chronic weight loss, unknown cough, congestive heart failure, previous participation in another keloid study, or a history of hypersensitivity reactions to either etanercept or TAC were also excluded, as well as patients who planned to receive live virus vaccines including, but not limited to bacillus Calmette-Guerin, mumps, rubella, small pox, chicken pox, and nasal influenza. During the screening visit, the of the patient's written informed consent was obtained. After a review of the patient's medical history and inclusion-exclusion criteria, a physical examination was performed on the patient. A urine pregnancy test was administered in all females of child-bearing age. Subjects were expected to show proof of a negative PPD test within the last year or were expected to undergo the PPD test to ensure negativity for the test.