Immune modifiers, novel treatments show promise for keloids

Dr. Berman

Miami - Keloids and scars may respond to immune response modifiers and experimental technologies such as a hydrogel scaffold or an antisense oligonucleotide, says Brian Berman, M.D., Ph.D.

“Why would anybody even consider using an immune response modifier for the treatment of scarring and keloids? When we insult the dermis - and we do that every day as dermatologists, with a scalpel - this activates a number of processes to induce the fibroblasts to release and synthesize more extracellular matrix components: collagen, fibronectin and glycosaminoglycans,” says Dr. Berman, voluntary professor of dermatology and cutaneous surgery, University of Miami Miller School of Medicine.

After the defect is filled, mechanisms by which the body tells the fibroblasts to shut down include the release of interferon, Dr. Berman says. Therefore, “The obvious thing to do would be to inject interferon into a keloid, and it should all go away. But that doesn’t really happen.”

Interferon injections make keloids smaller and softer, he says, but this does not eliminate them entirely. Clinicians’ attempts to maximize keloids’ response to treatment have included adding steroids to interferon, Dr. Berman says. In one study, investigators randomized 40 keloids to biweekly injections of intralesional triamcinolone acetonide or triamcinolone acetonide plus interferon alfa-2b for a total of 24 weeks.

“The combination therapy achieved significant reductions in keloid height (81.6 percent) and volume (86.6 percent) compared to baseline (Lee JH, Kim SE, Lee AY. Int J Dermatol. 2008;47(2):183-186). And it was interesting that the reductions in the steroid-injected group were not statistically significant,” Dr. Berman says.

Excising the keloids that remained, however, would only mean that they grew back later, sometimes larger than their original size, he adds.

Blocking recurrence

To see whether interferon could block such recurrences, Dr. Berman and colleagues retrospectively examined a group of patients who had had keloids excised from their earlobes. Investigators treated 43 patients with excision alone, 16 with interferon alfa-2b at the time of surgery, and 65 with triamcinolone acetonide at the time of surgery.

One-year postsurgery, interferon-treated patients had a recurrence rate of 19 percent, versus 51 percent among patients treated with excision alone; 58 percent of triamcinolone-treated keloids recurred (Berman B, Flores F. J Am Acad Dermatol. 1997;37(5 Pt 1):755-757). “Therefore, this study suggested that interferon may be able to block the recurrence of excised keloids,” Dr. Berman says.

For surgical scars, researchers applied topical imiquimod to scars left after bilateral breast reduction or augmentation in 15 patients.

“One of the scars was treated with imiquimod. The other side randomly was untreated, except for petrolatum. Within four weeks, it was very clear which side got which treatment,” Dr. Berman says.

The imiquimod-treated side became red as a result of inflammation generated by the body’s response to the drug, he explains. “But if you follow patients for a longer time period, the scarring did improve on the side that had been treated with imiquimod (Prado A, Andrades P, Benitez S, Umaña M. Plast Reconstr Surg. 2005;115(3):966-972).” Objective measures including the Strasser’s and Beausang scales validated that imiquimod produced less severe scarring than the untreated side, he says.

Other options

Investigators have tried antimetabolites including 5-fluorouracil for treating existing keloids, Dr. Berman says. In one study, investigators combined intralesional 5-fluorouracil and topical steroids to treat keloids and hypertrophic scars. Investigators randomized patients to eight weekly injections of either topical steroids or topical steroids plus 5-fluorouracil.

“At week 12,” he says, “keloids and scars in the combination group had significantly greater pliability, decreased redness, height, length, and width, and overall much better response than the steroid alone produced (Darougheh A, Asilian A, Shariati F. Clin Exp Dermatol. 2009;34(2):219-223. Epub 2008 Nov 6).” Overall, 55 percent of patients said they experienced at least 50 percent improvement, although investigators did not break down results for scars versus keloids.

In light of verapamil’s ability to stimulate procollagenase synthesis, Dr. Berman says, with this drug, “Theoretically we would be able to activate collagenase, which ultimately could break down the pre-existing collagen in a keloid.” To that end, a blinded, randomized study that included 54 keloids or hypertrophic scars pitted intralesional verapamil against intralesional triamcinolone acetonide, given every three weeks for six months. One year post-treatment, Dr. Berman says, verapamil-treated scars showed reduced erythema, height and width, along with greater pliability, as did those treated with triamcinolone acetonide (Margaret Shanthi FX, Ernest K, Dhanraj P. Indian J Dermatol Venereol Leprol. 2008;74(4):343-348).

In development

Therapies being developed include a hydrogel scaffold, Dr. Berman says. “It’s basically collagen that’s been heated,” he says. “That allows the intertwined strands of the collagen to dishevel. To keep those strands from re-annealing, you can add dextran. Dextran’s hydroxy groups are able to bind to the strands of gelatin so that the separated strands can be injected postsurgically.”

In a feasibility study, investigators injected the hydrogel after removing 26 keloids - most located on the earlobe - from 19 patients. Patients were treated intradermally with up to 2 mL of the scaffolding material for every 2.5 linear cm of scar. “Historically, the rate of keloid recurrence is somewhere between 40 percent and 100 percent on the earlobes,” Dr. Berman says. But this study showed a 12-month recurrence rate of 19.2 percent (Kim DY, Kim ES, Eo SR, et al. Plast Reconstr Surg. 2004;113(6):1668-1674).

Conversely, Dr. Berman says EXC 001 (Excaliard/Pfizer) is an antisense oligonucleotide that inhibits expression of connective tissue growth factor, which has been suggested to be involved in fibrosis and scarring.

“In a phase 2, randomized, double-blind, within-subject, placebo-controlled, dose-ranging study involving 28 patients, different doses of the agent were administered intradermally” to the abdomen before elective abdominoplasty, Dr. Berman says.

“The EXC 001 did block the production of CTGF, and other markers of fibrosis (Data on file, Excaliard),” he says. At 12 weeks postsurgery, treatment with EXC 001 significantly reduced the severity of fine-line scars and accelerated resolution of scarring versus placebo (p=0.003), according to Excaliard. Patients maintained these results out to the study’s conclusion at 24 weeks postsurgery. A phase 2 study in 21 patients with hypertrophic breast scars produced similar results, Dr. Berman says. DT

Disclosures: Dr. Berman is a consultant and/or investigator for Graceway, Medicis, Halscion, Excaliard and Capstone.