Vitiligo: Phototherapy, Drug Combination May Up Responses

Larry Hand

September 24, 2014

A combination of phototherapy and implantation of afamelanotide may be more effective than phototherapy alone in restoring skin pigmentation in individuals with vitiligo, according to an article published online September 17 in JAMA Dermatology. However, fewer patients completed the combination therapy compared with those in the phototherapy-only group in the randomized controlled trial.

Vitiligo, which causes white patches of skin from selective loss of epidermal melanocytes, affects from 1% to 2% of the general population.

Henry W. Lim, MD, from the Multicultural Dermatology Center at Henry Ford Hospital in Detroit, Michigan, and colleagues conducted a multicenter clinical trial involving 55 adult patients randomly assigned to receive either combination therapy or monotherapy. The patients were treated at 2 academic outpatient centers and 1 private dermatology practice.

Clinuvel Pharmaceuticals of Melbourne, Australia, funded the study and participated in its design.

The patients had a mean age of ~46 years, were racially diverse, and had dark white or dark brown or black skin, and most (86% combination; 81% monotherapy) had slow disease progression during the 3 months before entering the study.

The combination therapy consisted of afamelanotide, a synthetic version of the naturally occurring α-melanocyte-stimulating hormone, and narrowband ultraviolet B (NB-UV-B) phototherapy. Clinicians injected afamelanotide subcutaneously above the suprailiac crest once monthly for 4 months (days 28, 26, 84, and 112) in the form of a biodegradable polymer about the size of a grain of rice. Both groups were given NB-UV-B phototherapy 2 to 3 times per week for 6 months. Patients received a maximum of 72 treatments, and all patients were required to receive a minimum of 10 treatments each month. Monotherapy consisted of NB-UV-B phototherapy alone.

The researchers randomly assigned 28 patients to receive combination therapy and 27 patients to receive monotherapy, although 1 patient in each group dropped out. The researchers assessed skin changes using 2 scoring systems: The Vitiligo Area Scoring Index provides the percentage of vitiligo involvement for 6 body sites, ranging from 0% to 100%, and the Vitiligo European Task Force score assesses extent, staging, and spreading/progression of the disease at 5 body sites.

Both Groups Improved

Both groups experienced improvement in the degree of repigmentation, but the combination therapy group experienced greater degrees of repigmentation.

The combination therapy group experienced repigmentation (represented by a relative reduction in the Vitiligo Area Scoring Index) of 48.64% (95% confidence interval, 39.49% - 57.80%) at day 168 vs 33.26% (95% CI, 24.18% - 42.33%) in the group that received monotherapy.

Both groups achieved statistically significant improvement in disease extent, but the combination therapy group achieved it at day 56 compared with day 84 for the monotherapy group. In between-groups analysis, the combination therapy group demonstrated a superior response on days 140 and 168 (P ≤ .04).

There were no differences between the groups for disease staging, which assesses vitiligo severity.

Analysis of disease spreading found a statistically significant (P < .001) improvement in pigmentation in both groups, beginning on day 56. In between-groups analysis, the combination therapy group demonstrated a statistically superior response (P ≤ .03) beginning on day 56.

The combination group experienced faster repigmentation on the face and upper extremities, the most exposed body areas for vitiligo, with repigmentation on the face at 41 days compared with 61 days for the monotherapy group (P = .001). Repigmentation of the upper extremities occurred at 46.0 days compared with 69.0 days (P = .003), respectively.

The most common adverse effects was erythema, with 68% of patients in the combination group and 82% in the monotherapy group affected. In addition, 18% of patients in the combination group experienced nausea compared with none in the control group.

"Hyperpigmentation was subjectively experienced by all participants in the combination therapy group but only included as an adverse event if the patient complained of hyperpigmentation or if the hyperpigmentation had an effect on the patient," the authors write. "The 2 patients who complained of hyperpigmentation withdrew from the study for this reason." No cases of hyperpigmentation were reported in the monotherapy group.

The researchers chose the afamelanotide dose and frequency of injection on the basis of experience and did not conduct a dose-response study, which may be a limitation of the study. They also did not include an afamelonotide-only group.

They write that they chose patients with dark skin types "because of our collective clinical impression that dark-skinned patients in general tend to be more responsive to all types of treatments."

"Even with these limitations, the results of this multicenter, randomized study strongly indicate that administration of afamelanotide to patients receiving NB-UV-B phototherapy should be considered as an option that could significantly enhance the rate and the total surface area of repigmentation. Furthermore, our data suggest that patients with lesions on the face and upper extremities, and potentially those with darker skin, would have a more rapid response to the combination treatment," the researchers conclude.

Too Early...

However, the exclusion of lighter-skinned individuals could have a "potentially huge" effect, according to Jonathan I. Silverberg, MD, PhD, MPH, assistant professor of dermatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. The darker-skinned patients appeared to respond better than the lighter-skinned patients in the study, "so there may actually be less effectiveness in the 'real world' of patients" who have skin lighter than the patients in this study, he told Medscape Medical News.

"In addition, there may be significant differences in the characteristics between the monotherapy and combination therapy groups that raise questions about the validity of the randomization," he added. "In particular, there were more patients who were white and had slightly longer disease in the monotherapy, and these were also the patients that were less likely to respond overall to the drug."

He continued, "Overall, the work is very promising, but it is still early before we recommend this for all our vitiligo patients. There is no mention of power calculations, which makes it difficult to truly assess negative findings. Further, the patients were recruited from 3 sites that may not be generalizable to the entire vitiligo population.

"I would interpret this almost as a proof-of-concept efficacy trial. Larger-scale studies addressing safety and efficacy in broader patient populations are needed. More importantly, effectiveness studies are needed to determine if this works in the 'real-world.' The other caveat here is that afamelanotide monotherapy was not tested. So we don't know if afamelanotide monotherapy will work at all."

This research was partially designed and funded by Clinuvel Pharmaceuticals. Dr. Lim has reported that he has served as a consultant to Clinuvel Pharmaceuticals. The other coauthors and Dr. Silverberg have disclosed no relevant financial relationships.

JAMA Dermatol. Published online September 17, 2014. Abstract

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