Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea

Journal of Drugs in Dermatology, June, 2008 by James Q. Del Rosso, Joel Schlessinger, Philip Werschler

Rosacea is a chronic inflammatory dermatosis, but the exact etiology of rosacea remains unknown. It has been described as a result of "a disparate assortment of stimuli acting in concert on a genetically susceptible host" with a constitutional diathesis. (1) Among the many investigations into its pathophysiology, much interest has been focused on the role of the collagen-degrading matrix metalloproteinases (MMPs) and proteases that are involved in many aspects of tissue remodeling and local tissue inflammation. New research findings suggest that an upregulation of local inflammatory mediators play a key role in the pathophysiology of this chronic disease. (2), (3)

Tetracyclines have historically been used to treat rosacea. (4) No causative organisms have been definitively implicated as an etiologic factor in rosacea. Thus, it is thought that tetracyclines treat the disease primarily via multiple anti-inflammatory mechanisms. These mechanisms include MMP inhibition, reduced cytokine expression, and indirect inhibition of serine proteases. Animal model research has shown these effects to be exerted in the absence of antibiotic activity, and results from clinical trials support these findings. (4), (9)

Traditional doses of doxycycline (> 50 mg) can exert selection pressure, increasing the risk of bacterial resistance, and can alter normal commensal microflora. (7) A recent prospective, placebo-controlled, randomized, double-blind trial in 29 healthy volunteers demonstrated that daily administration of oral doxycycline 100 mg was associated with a significant increase in doxycycline-resistant nasopharyngeal flora measured at days 7 and 14, and continuing for at least 2 weeks after cessation of therapy. (8) In contrast, research has shown that even long-term treatment with an anti-inflammatory dose of doxycycline (40 mg delayed-re lease) does not alter susceptibility of bacteria to antibiotics in a 9-month trial. (5-7), (9)

Overview and Objectives

The following study evaluated the safety and efficacy of an anti-inflammatory dose of doxycycline (40 mg delayed-re-lease) administered once daily versus doxycycline 100 mg administered once daily in the treatment of moderate to severe rosacea for 16 weeks. In addition, both groups also applied topical metronidazole 1% gel once daily. ! his was a multi-center, outpatient, prospectively randomized, double-blind, active-control study of 91 subjects. The primary objective of the study was to evaluate, in subjects with inflammatory rosacea, the relative efficacy and onset of anti-inflammatory dose doxycycline (40 mg delayed-release), which does not exert an antibiotic effect, as compared to a conventional dose of doxycycline (100 mg daily), which does exert antibiotic activity. Additionally, an important objective of the study was to compare safety and adverse reactions between the 2 study arms.

Design

Subjects were randomized to receive daily administration of drugs in the following groups: 1.00 mg doxycycline and topical metronidazole 1 % gel (Group 1) and 40 mg delayed-release doxycycline and topical metronidazole 1% gel (Group 2). Both the doxycycline 100 mg capsules and 40 mg delayed-release capsules were over encapsulated to ensure the capsules were indistinguishable during administration and maintain a double-blind study.

Inclusion/Exclusion Criteria

The study population included healthy, postpubescent males and females > 18 years of age with inflammatory (papulopustular) rosacea, 8 to 40 papules and pustules, < 2 nodules, a score of 2 to 5 on the Investigator's Global Assessment (IGA) (Table 1), a total erythema score of 5 to 20 with at least 1 pentad (1 of 5 facial areas) specific score of [plus or minus]2 on the Clinician's Erythema Assessment (CEA) scale (Table 2), and the presence of telangiectasia. Conventional precautions regarding the use of contraceptives, negative pregnancy test, and nonlactation were applied.

Table 1. Investigator's Global Assessment.

Score  Definition   Assessment guideline

0      Clear        Skin is completely clear of inflammatory lesions

1      Near clear   1-4 papules and pustules; no nodules

2      Mild         5-10 papules and pustules; no nodules

3      Moderate     11-17 papules and pustules; 0 or 1 nodule
                    may be present

4      Severe       18-25 papules and pustules; 1 or 2 nodules must
                    be present; perilesional erythema is present

5      Very severe  >25 papules and pustules; nodules must be present;
                    perilesional erythema plus edema are a hallmark of
                    this patient

Table 2. Clinician's erythema assessment scale.

Score  Definition   Assessment guideline

0      None         No redness present
1      Mild         Slight pinkness
2      Moderate     Definite redness
3      Significant  Marked erythema
4      Severe       Fiery redness

Exclusion criteria included changes in hormonal contraception methods within 4 months of baseline, the use of any rosacea treatments within 2 weeks of baseline, subjects with a known sensitivity to study drugs, and use of clinically significant concomitant drug therapy including corticosteroids and vasodilatory agents.

Demographics

Subject demographics are summarized in Table 3. A total of 24 subjects discontinued the study prematurely (Table 4).

Table 3. Subject demogtaphics (N=91).

           Group 1 (100 mg) subjects   Group 2 (40 mg) subjects
                    (n=47)                     (n=44)

Completed             37                         30

Gender

  Male                12                         15
  Female              35                         29

Race

  Caucasian           44                         43
Mean age (years)      45.2                       44.3

Table 4. Reasons for discontinuation.

                          Group 1:n (%)  Group 2: n (%)  Total: N (%)

Discontinued from study     10 (21.3)       14 (31.8)      24 (26.4)
Adverse or serious           4 (8.5)         5 (11.4)       9 (9.9)
adverse event
Protocol violation           1 (2.1)         3 (6.8)        4 (4.4)
Lost to follow-up            0 (0.0)         4 (9.1)        4 (4.4)
Patient Withdrew consent     4 (8.5)         0 (0.0)        4 (4.4)
Other                        1 (2.1)         2 (4.5)        3 (3.3)