Biological therapies

Costas Papageorgiou MD, London March 2014

Skin wound healing in humans, our body’s “glue” is a highly complex process requiring the collaborative efforts of many different tissues and cell lineages. With advances in the knowledge of wound healing, as well as the development of better materials and techniques, many options have become available in the treatment of patients with unsightly scars. Nevertheless, no technique has been devised to allow total and permanent removal or effacement of scars. Pharmacologic manipulation of the scar aims to alter cell metabolism at specific sites. Patients should understand that the goal of scar revision or remodeling is to improve the appearance and the acceptability of the scar.

Corticosteroids

For many years, intralesional corticosteroid injections have been established in the reduction of hypertrophic scars and keloids, alone or in combination with other therapeutic options. Corticosteroids are known primarily as gene regulators with anti-inflammatory effects. It is well known that inflammation related release of modulators plays a significant role in the rate and quality of wound healing.

Steroids decrease fibroblast proliferation, reduce blood vessel formation, and interfere with fibrosis by inhibiting extracellular matrix protein gene expression: in specific they down regulates pro-alpha 1 collagen gene.  By decreasing the production of collagen, dermal thickening is modulated and a smaller scar is created. The most commonly used preparations are Triamcinolone Acetonide (Kenalog) and Triamcinolone Diacetate (Aristocort) at a dose of 5 to 10mg/ml injected into the target area every 3 to 6 weeks.

Antimetabolites

Intralesional 5 Fluorouracil (5-FU) has been described as an effective treatment modality in the management of dermal scars, particularly for the treatment of hypertrophic scars, keloids and soft tissue retraction.

5 Fluorouracil is an anti-metabolite that inhibits cell proliferation through the disruption of DNA synthesis and inhibition of collagen production. 5-FU only works on cells that are metabolically active and proliferating, instead of causing collateral damage to surrounding cells. The main mechanism of action relies on inhibition of a key enzyme in the DNA synthesis process, named thymidilate synthetase  and resulting in specific inhibition of proliferating and synthetically active cells that cause fibrosis. The relative specificity directed to actively synthetic or proliferating cells minimizes clinical tissue toxicity and side effects.

The efficacy of 5-FU in the management of scars may also be related to its capacity to interfere with transforming growth factor-b (TGF-b) and type I collagen gene expression in dermal fibroblasts. Abnormally excessive accumulation of type I collagen has been found in keloids and hypertrophic scars, which is believed to play a pathological role in these exuberant scar responses. TGF-b is though to be the main factor leading to tissue fibrosis secondary to its induction of collagen gene expression.

Cocktail injections

A combination of 5-FU with Triamcinolone acetonide and serial injections augment the modulation effect on the target zone and can prevent or ameliorate the scar.  5-FU acts on a slightly different pathway than steroids do, inhibits DNA production and decreases the proliferation of the infiltrating fibroblasts in the target area, ultimately lowering production of collagen and decreasing the density of the extracellular matrix.

Combining both agents in a 3:1 ratio (75% 5-FU 50 mg/ml and 25% Kenalog 5mg/ml) prompts a quicker resolution of the scar, allowing the inflammatory process and repair to continue without massive, or further, infiltration of fibroblasts. In addition by lowering the dose of steroids there is less incidence of fat atrophy or hypopigmentation. This approach can have a powerful effect especially in lower eyelid revision surgery as it can modulate the active status of fibroblasts in multi-operated and sensitive areas with pre-existing scarring.

FDA status and off-label use of anti-metabolites  

5-Fluorouracil was approved by the Food and Drug Administration (FDA) for the treatment of various types of cancer.  Upon approval, the drug manufacturer produces a “label” that explains its use.  Once a drug is approved by the FDA, physicians can use it for other purposes “off-label” as part of the practice of medicine if they are well-informed about the product, base its use on firm scientific method and sound medical evidence, and maintain records of its use and effects.

The physician’s decision to use this agent is based on the evaluation of the advantages and potential disadvantages in each individual case. 5-FU has not received FDA approval for the treatment of scars although physicians have been using this drug off label for over a decade and several clinical studies have demonstrated its beneficial effect.