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Patients with severe acne had significantly greater improvement when topical adapalene/benzoyl peroxide (Epiduo) was added to oral doxycycline, according to results of a randomized clinical trial.

The absolute difference in total lesion clearance averaged 23% at the end of the study. The superiority of combination therapy became evident as early as week two, investigators reported in the February issue of Cutis.

"Patients saw some improvement fairly quickly," Linda Stein Gold, MD, of Henry Ford Health System in Detroit, said in an interview. "Over the first month, they definitely started to see their bumps flatten down. By the end of the entire study, they had a nice improvement, as 31% of the patients were clear or almost clear."

"It's nice because it really did target that more severe patient population," she added. "We don't have a lot of studies that really look at that particular population."

Patients with severe acne vulgaris have few treatment options other than oral isotretinoin, which affects all major acne-related pathogens and is the treatment of choice for severe forms of acne, including recalcitrant nodular acne or acne conglobata (J Am Acad Dermatol 2003; 49(suppl 1): S1-S37). Isotretinoin can produce a number of adverse effects.

Recently, the combination of a topical retinoid plus benzoyl peroxide and an oral antibiotic was recommended as first-line therapy for all but the most severe forms of acne vulgaris (J Am Acad Dermatol 2009; 60(suppl 5): S1-S50). However, use of oral antibiotics to treat acne has raised concerns about the potential for development of antibiotic resistance by Propionibacterium acnes and other mucocutaneous bacteria. Benzoyl peroxide has broad-spectrum antimicrobial activity to which P. acnes has not developed resistance, and may prevent bacterial resistance from developing when added to oral antibiotic therapy.

Adapalene has anticomedogenic, anti-inflammatory, and comedolytic properties. Its use in combination with benzoyl peroxide is consistent with recommendations for topical acne therapy and does not promote antibiotic resistance, the authors wrote. Moreover, the combination of adapalene and doxycycline has resulted in greater and more rapid improvement in severe acne compared with doxycycline alone (Skinmed 2005; 4: 138-46).

Although recommended for treatment of all but the most severe acne cases, combination therapy had not been compared with antibiotic monotherapy in a randomized clinical trial. To address the lack of comparative data, investigators at 35 centers in the U.S. and Canada conducted a randomized clinical trial to compare doxycycline alone and with fixed-dose adapalene/benzoyl peroxide in patients with severe acne.

Principal eligibility criteria for the trial were an investigator's global assessment (IGA) score of 4 (severe acne) and a minimum of 20 inflammatory lesions, 30 to 120 noninflammatory lesions, and no more than three nodulocystic lesions. Patients were allocated to oral doxycycline plus either fixed-dose adapalene/benzoyl peroxide or gel vehicle and treated for 12 weeks.

The primary efficacy endpoint was the percentage change from baseline in total lesion count. Secondary endpoints included percentage change in inflammatory and noninflammatory lesion counts and change in IGA score (0=clear, 5=very severe or highly inflammatory acne covering the face). A subset of patients was evaluated by ultraviolet fluorescence photography for the presence of P. acnes.

Investigators randomized 459 patients to oral doxycycline plus topical adapalene/benzoyl peroxide or gel vehicle. The patients had an average of 37 inflammatory lesions and 63 noninflammatory lesions. Follow-up visits occurred at two, four, eight, and 12 weeks.

The overall superiority of the combination therapy emerged by week two, as total lesion clearance averaged 21% versus 13% for doxycycline alone (P<0.001). By week 12, patients allocated to the combination had an average clearance of 64% versus 41% with doxycycline plus vehicle (P<0.001).

The mean improvement in inflammatory lesions increased from 27% at week two to 72% at week 12 in the doxycycline-adapalene/benzoyl peroxide arm compared with 22% and 48% in the control arm (P=0.004, P<0.001, respectively). Combination therapy also led to significantly more improvement in noninflammatory lesion count, 17% versus 10% at week two (P<0.001), and 61% versus 40% at week 12 (P<0.001).

The proportion of patients rated as clear or nearly clear by IGA averaged 9.9% and 2.6% at eight weeks with the combination and control arms, respectively (P=0.001). At week 12 the improvement stood at 31% with the combination and 8.4% with the control (P<0.001).

UV fluorescence photography in 38 patients showed a mean reduction in P. acnes total spot area of 60.3% at week four and 73.6% at week 12 with doxycycline and adapalene/benzoyl peroxide combination therapy compared with 22% and 14% in the control arm.

The investigators speculated that the decreased reduction in the P. acnes total spot area among patients in the control group between weeks four and 12 might reflect emergence of resistance to doxycycline.

Tolerability was good and similar in both treatment arms. The overall incidence of adverse events was 11.8%, primarily attributable to gastrointestinal complaints associated with doxycycline (9.6%).

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