Rosacea

Propranolol, doxycycline and combination therapy for the treatment of rosacea

doi: 10.1111/1346-8138.12687 Journal of Dermatology 2015; 42: 6469

ORIGINAL ARTICLE

Propranolol, doxycycline and combination therapy for the treatment of rosaceaJung-Min PARK,1 Je-Ho MUN,1 Margaret SONG,1 Hoon-Soo KIM,1 Byung-Soo KIM,1,2Moon-Bum KIM,1,2 Hyun-Chang KO1,31Department of Dermatology, School of Medicine, Pusan National University, 2Biomedical Research Institute, Pusan National University Hospital, and 3Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Busan, Korea

ABSTRACTDoxycycline is the standard systemic treatment for rosacea. Recently, there have been a few reports on b-adrenergic blockers such as nadolol, carvedilol and propranolol for suppressing flushing reactions in rosacea. To our knowledge, there are no comparative studies of propranolol and doxycycline, and combination therapy using both. The aim of this study was to investigate and compare the efficacy and safety of monotherapy of propranolol, doxycycline and combination therapy. A total of 78 patients who visited Pusan National University Hospital and were diagnosed with rosacea were included in this study. Among them, 28 patients were in the propranolol group, 22 the doxycycline group and 28 the combination group. We investigated the patient global assessment (PGA), investigator global assessment (IGA), assessment of rosacea clinical score (ARCS) and adverse effects. Improvement in PGA and IGA scores from baseline was noted in all groups, and the combination therapy was found to be the most effective during the entire period, but this was statistically insignificant. The reduction rate of ARCS during the treatment period was also highest in the combination group (57.4%), followed by the doxycycline group (52.2%) and the propranolol group (51.0%). Three patients in the combination group had mild and transient gastrointestinal disturbances but there was no significant difference from the other groups. We con- clude that the combination therapy of doxycycline and propranolol is effective and safe treatment for rosacea and successful for reducing both flushing and papulation in particular.Key words: combination, doxycycline, propranolol, rosacea, treatment.INTRODUCTIONRosacea is a common chronic dermatological condition characterized by recurrent episodes of exacerbation and remission. It usually affects individuals between the ages of 30 and50 years and women are more affected than men.1,2 Classifi-cation of rosacea includes erythematotelangiectatic (ETR), papulopustular (PPR), phymatous and ocular subtypes.35 ETR is characterized by flushing and persistent central facial erythema and PPR presents with persistent facial erythema and transient papules or pustules, or both, in a central facial distribution.3The etiology of rosacea is still unknown and this condition has led to a therapeutic challenge. Although there is no cura- tive treatment for rosacea, tetracycline compounds have been the mainstay therapy and among them, tetracycline and doxycycline are the standard systemic therapy of rosacea. Doxycy- cline shows anti-inflammatory effects and antioxidant properties. It exhibits superior pharmacokinetic advantages and lesser toxicity than tetracycline, so it is widely used forrosacea.6

Beta-adrenergic blockers nadolol, carvedilol and propranolol have been reported to suppress flushing reactions, particularly when associated with anxiety.7,8 Its therapeutic mechanism is to block the b2-adrenergic receptor on the smooth muscle of cutaneous arterial blood vessels resulting in vasoconstriction.To our knowledge, there is no comparative study between propranolol and doxycycline for rosacea and also no previous report on the efficacy of combination therapy of propranolol and doxycycline. Therefore, we investigated the efficacy and safety of the monotherapies of propranolol and doxycycline, and the combination therapy of propranolol and doxycycline.METHODSPatientsRosacea patients aged above 18 years who visited the outpa- tient clinic of the Department Of Dermatology at Pusan National University Hospital from August 2008 to August 2012 were enrolled. The exclusion criteria were patients who hadbeen treated with topical and systemic medications which can

Correspondence: Hyun-Chang Ko, M.D., Department of Dermatology, School of Medicine, Pusan National University, Geumoh-ro 20, Mulgeum-eup, Yangsan-si, Busan, Gyeongsangnam-do 626-770, Korea. Email: [email protected] 23 January 2014; accepted 29 September 2014.

affect the symptoms of rosacea (e.g. other antibiotics, isotretinoin, corticosteroid, cyclosporin) or with laser that targeted the vasculature, such as flash pumped pulsed dye laser and intense pulsed light, for the previous year. For the doxycycline group, pregnant or lactating women and patients with accom- panying chronic renal failure, hepatic failure and myasthenia gravis were excluded. For the propranolol group, patients with bronchial asthma, hypotension, bradycardia, atrioventricular block, sinoatrial block and congestive heart failure were excluded.

MethodsThe study protocol was approved by the Pusan National Uni- versity Hospital institutional review board.At their first visit, the patients age, sex and disease duration were recorded and the severity of the rosacea was assessed. Subtypes of rosacea (ETR and PPR), distribution, aggravating factors and symptomatology were also checked.The global change assessment in the rosacea condition, as assessed by the patient global assessment (PGA) andinvestigator global assessment (IGA), was compared withTable 1. Demographics and clinical manifestations of the patientsPropranolol group (n = 22)Doxycycline group (n = 15)Combination group (n = 26)Total(n = 63)

Age, years (mean SD) Sex (M : F)55.7 12.72:947.4 11.84:1148.4 12.64:950.6 12.816:47

Subtype (ETR : PPR)19:34:119:1732:31

Duration (months, mean SD)33.3 46.525.3 30.129.2 32.629.7 37.0

Frequency in a dayDistribution, n (%)3.0 2.42.0 1.72.0 1.02.3 1.8

Whole face2 (9.1)1 (6.7)16 (61.5)19 (30.2)

Cheek20 (90.9)14 (93.3)21 (80.8)55 (87.3)

Nose2 (9.1)7 (46.7)15 (57.7)24 (38.1)

Chin3 (13.6)5 (33.3)16 (61.5)24 (38.1)

Forehead4 (18.2)2 (13.3)14 (53.8)20 (31.7)

Periocular3 (13.6)2 (13.3)3 (11.5)8 (12.7)

Aggravation factor (n, compound factor) (%)

Heat11 (50.0)8 (53.3)13 (50.0)43 (68.3)

Emotional change8 (36.4)9 (60.0)13 (50.0)30 (47.6)

Exercise or bathing6 (27.3)6 (40.0)6 (23.1)18 (28.6)

Alcohol5 (22.7)3 (20.0)6 (23.1)14 (22.2)

Cold4 (18.2)3 (20.0)3 (11.5)10 (15.9)

Sun exposure3 (13.6)04 (15.4)7 (11.1)

Other1 (4.5)001 (1.6)

Symptom (n, compound factor) (%)

Flushing18 (81.8)12 (80.0)21 (80.8)51 (81.0)

Itching2 (9.1)3 (20.0)3 (11.5)8 (12.7)

Tingling5 (22.7)1 (6.7)4 (15.4)10 (15.9)

Burning1 (4.5)001 (1.6)

ETR, erythematotelangiectatic; PPR, papulopustular; SD, standard deviation.(a) (b)

Figure 1. (a) Mean physician global assessment and (b) investigator global assessment scores of rosacea patients through12 weeks.

Figure 2. Mean assessment of rosacea clinical score (ARCS)

through 12 weeks.Table 2. Mean scores of primary features in assessment of rosacea clinical scoreDoxycycline groupCombination group*Baseline vs 12 weeks. SD, standard deviation.baseline and scored on a 7-point scale, with +3 being markedly improved, +2 moderately improved, +1 mildly improved,0 unchanged, 1 mildly worse, 2 moderately worse and 3 markedly worse.9 The assessment of rosacea clinical score (ARCS) was also checked.4 PGA and IGA were checked at weeks 2, 4, 8 and 12 and ARCS at baseline and at weeks 4, 8 and 12. Laboratory tests were done for com- plete blood cell count, liver and renal functions, and urinaly- sis before and during the treatment.The patients with rosacea were divided into three groups:28 patients treated with propranolol 10 mg three times a day(propranolol group); 22 patients treated with doxycycline100 mg two times a day (doxycycline group); and 28 patients treated with propranolol 10 mg three times a day and doxycycline 100 mg two times a day (combination group).Statistical analysisThe KruskalWallis test was performed to evaluate differences between the three groups using the PASW for Windows (IBM, Armonk, NY, USA). Students two-sample t-test was performed to estimate the differences of the score for the primary features of ARCS between baseline and after 12 weeks of treatment. Statistical significance was defined as P < 0.05.RESULTSOf the 78 subjects enrolled, 63 completed the study. In the propranolol group, 78.6% (22/28) of patients completed the study. Among the six patients who dropped out, other systemic agents were added in the treatment of five patients (three with doxycycline, one with minocycline, one with isotre-

effect on flushing during the study period. In the combination group, 92.9% (26/28) of the patients completed the study. One patient changed doxycycline to roxithromycin and the other added laser therapy because of unsatisfactory effects.Mean age was 50.6 years (range, 1676), 47 patients were female and 16 were male. According to the subtypes, 32 patients were ETR patients and 31 PPR. Mean duration of disease was 29.7 months (range, 1200) (Table 1).

Mean PGA scores in propranolol, doxycycline and the combination group were 1.7, 1.9 and 2.0 after 12 weeks of treatment, respectively. Mean IGA scores were the same as the mean PGA scores at the end of the study. Propranolol and the combination group tended to show rapid improvement within4 weeks but the doxycycline group caught up with the improvement of these groups between 4 and 8 weeks (Fig. 1). However, there were no statistically significant differences among the three groups.Mean ARCS were 10.2, 11.3 and 11.6 in the propranolol, doxycycline and combination groups, respectively, at baseline and decreased to 5.0, 5.4 and 5.5 after the 12-week treatment. Reduction ratio of ARCS between baseline and the end of the study was 51.0%, 52.2% and 57.3% in the propranolol, doxycycline, and combination groups, respectively (Fig. 2). There also were no statistically significant differences among the three groups at baseline and during the treatment period.Table 3. Change of percentage in total assessment of rosacea clinical score from baseline(a) (b) (c)Figure 3. Serial changes of rosacea patients after 12 weeks of treatment. (a) A 72-year-old woman (erythematotelangiectatic) in the propranolol group. (b) A 41-year-old man (papulopustular) in the doxycycline group. (c) A 55-year-old woman (papulopustular) in the combination group.Table 4. Adverse effects during the studyPropranolol group (%)Doxycycline group (%)Combination group (%)Total (%)

Adverse effect2 (9.0): dyspepsia (n = 1)

headache (n = 1)3 (20.0): gastrointestinal disturbance3 (11.5): gastrointestinal disturbance8 (12.7)

The primary features in ARCS were analyzed separately to assess the specific effects of each treatment regimen. In the propranolol group, the papules and pustules score showed a partial reduction while the flushing score showed the biggest decrease after the 12-week treatment, with statistical significance. In the doxycycline and combination groups, all primary feature scores showed a significant decline after the 12-week treatment, and the papules and pustules scores revealed the biggest drop at the end of the period (Table 2). In Table 3, changes of percentage in total ARCS from baseline were analyzed. At weeks 4 and 12, the combination group showed a significantly higher percentage change than other groups. The propranolol group demonstrated a significantly lower percentage change than the doxycycline group at week 4, but they showed similar percentage change after week 8 (Fig. 3).

Adverse events were reported in 12.7% (8/63) of the patients. Dyspepsia and headache were experienced in 4.5% (1/22) of the patients in the propranolol group. Gastrointestinal disturbances were found in 20.0% (3/15) and 11.5% (3/26) of the patients in the doxycycline and the combination group, respectively. These side-effects were transient and self-limited and there were no serious events or discomfort that made the patients stop the treatment (Table 4).

DISCUSSIONRosacea is a chronic inflammatory skin disease and yet the underlying pathophysiology is not entirely known.10 It is characterized by persistent erythema, telangiectasia, papules and even pustules on the face.11 Various causes have been found to act as aggravation factors of rosacea, such as emotional change, heat, exercise, bathing, alcohol, cold and sun exposure, and it is difficult to avoid all provocative stimuli.12,13 Thus, the therapeutic approach of rosacea depends more on the clinical subtype than a known etiology.14Treatment for rosacea includes topical anti-inflammatory agents, topical or systemic antibacterials, retinoids and laser therapy.14 Oral tetracycline, particularly tetracycline and doxycycline, have been the mainstay of treatment of rosacea for a long time. They are especially effective in treating PPR but also ETR through inhibition of leukocyte-derived matrix-degrading metalloproteinases.15,16 Flushing usually does not respond to conventional rosacea treatment. Therefore, treatment of ETR with severe flushing is challenging although some successes with beta-blockers such as nadolol, carvedilol and propranolol have been reported.7,17 Propranolol has not demonstrated objective evidence for direct effects on cutaneous blood vessels in flushing, but a previous study reported that 88.9% (8/9) of patients showed improvement of their symptoms and had fewer flushing episodes while taking propranolol.7 The mechanism

of propranolol in treating ETR is supposed to be by blocking the b2-adrenergic receptor on the smooth muscle of cutaneous arterial blood vessels, resulting in vasoconstriction.5 Moreover,reactive oxygen species released by local inflammatory cells which contribute to the inflammation in rosacea can be controlled by the antioxidant properties of propranolol.18,19Although ETR is characterized by flushing and PPR is characterized by papules and pustules, symptoms of both subtypes can be shared in mild form. As previously described, it is known that doxycycline is more effective in PPR and propranolol seems to be more effective in ETR. Hence, we conducted this study to compare the efficacy between the monotherapies of doxycycline and propranolol and the combination of both.In the present study, the propranolol group showed a faster response than the doxycycline group regarding PGA and IGA within the first 4 weeks. Both groups demonstrated the same effectiveness at week 8 and, finally, the doxycycline group had higher PGA and IGA scores than the propranolol group by the end of the study. The doxycycline group showed drastic improvement between weeks 4 and 8. The combination group showed the best effect among the three groups during the entire period and also rapid improvement within the first4 weeks.Regarding ARCS, the combination group had the highest reduction ratio among the three groups. In the analysis of primary features, after 12 weeks of therapy, with the exception of papules and pustules in the propranolol group, all of the parameters showed statistically significant improvement compared with baseline. The propranolol group showed an especially rapid response in flushing, and the doxycycline group showed a notably faster effect in papules and pustules. The combination treatment was effective in both flushing and papules and pustules. Regarding percentage change of total ARCS from baseline, the combination group demonstrated significantly higher change at first visit and after 12 weeks. This result indicates that combination therapy of doxycycline and propranolol can show fast and constant improvement of ARCS in rosacea patients during 12-week treatment compared with monotherapy.Our results show that the combination of doxycycline200 mg/day and propranolol 30 mg/day significantly reduced both flushing (70%) and papulation (82%) in rosacea over a period of 12 weeks. Wise20 reported that doxycycline 40 mg/ day improved 80100% of inflammatory lesions and reduced erythema by 50%. Ertl et al.21 demonstrated that isotretinoin10 mg/day for 16 weeks showed 75% improvement of papular lesions and 38% reduction in erythema. Compared with previous studies, combination therapy of doxycycline and propranolol is appropriate for patients with both flushing and papulation.The side-effects were minimal and well-tolerated in all groups. There were no side-effects of hypotension and bradycardia although all of the patients who were treated with propranolol were normotensive. No cases of photosensitivity were reported in both the doxycycline and combination group.This study is subject to a number of limitations: there was a disproportionate number of patients in each subtype; the cohort size of the patients was small; and the study was non- randomized, non-blinded and non-placebo controlled. Particu- larly, patient groups in this study were divided according to treatment modality and rosacea subtypes are not equally dis- tributed among the three treatment groups. It will be valuable to attempt to analyze treatment groups classified by subtype because the rosacea treatments are chosen by subtypes. However, the number of patients per subtype group in this study was small and it was difficult to perform a statistical analysis. However, we believe our results add further data to demonstrate the high effectiveness of the combination therapy of doxycycline and propranolol in rosacea patients. Random- ized controlled studies with a large series will be helpful to more accurately investigate the efficacy and safety of the combination therapy of doxycycline and propranolol. This study is the first to present data about the combination therapy of doxycycline and propranolol, showing that it is more effective than monotherapy, especially in 4 weeks and after 12 weeks of treatment. The treatment regimen was also well tolerated.CONFLICT OF INTEREST: The authors have no conflict of interest to declare.REFERENCES1 Powell FC. Clinical practice. Rosacea. N Engl J Med 2005; 352:793803.2 Berg M, Liden S. An epidemiological study of rosacea. Acta DermVenereol 1989; 69: 419423.3 Wilkin J, Dahl M, Detmar M et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol2002; 46: 584587.

4 Wilkin J, Dahl M, Detmar M et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol2004; 50: 907912.5 Lee JY. Rosacea: clinical aspects, pathogenesis and treatment.Dermatol Sinica 2005; 23: 121130.6 Valent n S, Morales A, Sa nchez JL, Rivera A. Safety and efficacy of doxycycline in the treatment of rosacea. Clin Cosmet Investig Dermatol 2009; 2: 129140.7 Craige H, Cohen JB. Symptomatic treatment of idiopathic and rosacea associated cutaneous flushing with propranolol. J Am Acad Dermatol 2005; 53: 881884.8 Hsu CC, Lee JY. Carvedilol for the treatment of refractory facial flushing and persistent erythema of rosacea. Arch Dermatol 2011;147: 12581260.9 Draelos ZD, Ertel K, Berge C. Niacinamide-containing facial mois- turizer improves skin barrier and benefits subjects with rosacea. Cutis 2005; 76: 135141.10 Conde JF, Yelverton CB, Balkrishnan R et al. Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. J Drugs Dermatol 2007; 6: 495498.11 Marks R. The enigma of rosacea. J Dermatolog Treat 2007; 18:326328.12 Lee SY, Choi JH, Sung KJ, Moon KC, Koh JK. A clinical study of112 patients with rosacea. Korean J Dermatol 2001; 39: 636642.13 Oztas MO, Balk M, Ogus E et al. The role of free oxygen radicals in the aetiopathogenesis of rosacea. Clin Exp Dermatol 2003; 28: 188192.14 Alikhan A, Kurek L, Feldman SR. The role of tetracyclines in rosacea. Am J Clin Dermatol 2010; 11: 7987.15 Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 2006; 54: 258265.16 Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin 2007; 25: 133135.17 Hsu CC, Lee JY. Pronounced facial flushing and persistent erythema of rosacea effectively treated by carvedilol, a nonselec- tive b-adrenergic blocker. J Am Acad Dermatol 2012; 67: 491493.18 Mak IT, Weglicki WB. Potent antioxidant properties of 4-hydroxyl- propranolol. J Pharmacol Exp Ther 2004; 308: 8590.19 Jones D. Reactive oxygen species and rosacea. Cutis 2004; 74(Suppl): 1720, 324.20 Wise RD. Submicrobial doxycycline and rosacea. Comp Ther 2007;33: 7881.21 Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Derma- tol 1994; 130: 319324.

Baseline4 weeks8 weeks12 weeksP*Propranolol group (mean SD) Flushing

2.4 0.5

1.7 0.5

1.3 0.6

0.7 0.6

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