Systemic isotretinoin in the treatment of rosacea – doxycycline‐ and placebo‐controlled,randomized clinical study

Background: Systemic isotretinoin has been known for decades to be effective in the treatment of severe forms of rosacea, but it must be used off‐label because of the lack of evidence‐based data. Patients and Methods: 573 patients with rosacea subtype II and III received one of three different dosages of isotretinoin (0.1 mg, 0.3 mg, or 0.5 mg per kg body weight), doxycycline (100 mg daily for 14 days, then 50 mg daily) or placebo in a double‐blinded, randomized way for 12 weeks in 35 German centers. Results: Isotretinoin 0.3 mg/kg proved to be the most effective dose with significant superiority versus placebo. Isotretinoin 0.3 mg/kg showed also significant non‐inferiority versus doxycycline with reduction of lesions of 90 % compared to 83 % with doxycycline. Investigators diagnosed complete remission in 24 % and marked improvement in further 57 % of patients with isotretinoin treatment, in contrast to remission in 14 % and marked improvement in 55 % of patients treated with doxycycline. Isotretinoin 0.3 mg/kg revealed a similar safety profile as for the treatment of acne. Isotretinoin 0.5 mg/kg showed more dermatitis facialis as compared to 0.3 mg/kg. Conclusions: Isotretinoin 0.3 mg/kg is an effective and well‐tolerated therapy option for the treatment of rosacea subtype II and III and can therefore be used successfully as an alternative to therapy with oral antibiotics.     

Prognosis of 234 rosacea patients according to clinical subtype: The significance of central facial erythema in the prognosis of rosacea

Rosacea has a wide spectrum of clinical features, which include persistent facial redness, flushing, telangiectasia, inflammatory papules/pustules, hypertrophy and/or ocular features. The prognosis of rosacea according to clinical subtype has not been evaluated. We analyzed the prognosis of rosacea in 234 patients, which included 120 patients with mixed subtype, 75 with the erythematotelangiectatic rosacea subtype and 39 with the papulopustular rosacea (PPR) subtype. The prognosis of rosacea was classified as: (i) no improvement; (ii) partial remission; and (iii) complete remission. The frequencies of complete remission, time to complete remission and 1‐year complete remission rate were compared between subtypes. Follow‐up periods ranged 2–72 months (median follow‐up, 17.5). Aggravation of the disease was found in 50.4% of patients during follow up. Partial or complete remission was noted in 61.5% and 20.9% of patients, respectively. The median time to complete remission was 56.0 months. The prognosis of disease was more favorable for patients with the PPR subtype than for patients with other subtypes with respect to the frequency of complete remission, median time to complete remission and the 2‐year complete remission rate. In conclusion, papulopustular rosacea without remarkable centrofacial erythema showed a more favorable prognosis than other subtypes. Erythematotelangiectatic lesions in rosacea patients present a challenge for the treatment of rosacea.     

Pathogenese,Klinik und aktuelle Therapie der Rosazea

Rosacea is a common chronic inflammatory disease, especially in patients with fair skin and positive family history. Typical locations are forehead, nose, cheeks and chin; the periorbital region is usually not involved. Clinical features can be very heterogeneous. Besides different subtypes (erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea), which often overlap, various special forms of rosacea exist. Up to 60?% of patients with cutaneous rosacea suffer from ocular rosacea. In Germany, brimonidine, metronidazol, azelaic acid, and ivermectin are approved for topical therapy of rosacea; for systemic therapy, doxycycline at a subantimicrobial dose (40 mg/day) is the only approved substance. In case of resistance to this therapy, contraindications or side effects, various alternative therapies are available, however off-label.     

Current topical and systemic approaches to treatment of rosacea

Rosacea is a common, often overlooked, chronic facial dermatosis characterized by intermittent periods of exacerbation and remission. Clinical subtypes and grading of the disease have been defined in the literature. On the basis of a genetic predisposition, there are several intrinsic and extrinsic factors possibly correlating with the phenotypic expression of the disease. Although rosacea cannot be cured, there are several recommended treatment strategies appropriate to control the corresponding symptoms/signs. In addition to adequate skin care, these include topical and systemic medications particularly suitable for the papulopustular subtype of rosacea with moderate to severe intensity. The most commonly used and most established therapeutic regimens are topical metronidazole and topical azelaic acid as well as oral doxycycline. Conventionally, 100–200 mg per day have been used. Today also a controlled release formulation is available, delivering 40 mg per day using non-antibiotic, anti-inflammatory activities of the drug. Anti-inflammatory dose doxycycline in particular allows for a safe and effective short- and long-term therapy of rosacea. Topical metronidazole and topical azelaic acid also appear to be safe and effective for short-term use. There are indications that a combined therapy of anti-inflammatory dose doxycycline and topical metronidazole could possibly have synergy effects. Further interesting therapy options for the short- and long-term therapy of rosacea could be low-dose minocycline and isotretinoin; however, too little data are available with regard to the effectiveness, safety, optimal dosage and appropriate length of treatment for these medications to draw final conclusions.

Conflicts of interest

None declared.     

Ophthalmic Rosacea: Case Report in a Child and Treatment Recommendations

We report a rare case of rosacea with ocular involvement in a child that remitted with prolonged anti‐inflammatory oral tetracycline therapy and provide general expert recommendations. A 14‐year‐old girl presented with discrete papules and pustules on both cheeks with blepharitis and conjunctivitis. Ophthalmologic examination confirmed bilateral severe blepharitis, as well as a corneal infiltrate in the right eye with additional neovascularization. The diagnosis of rosacea with ocular involvement was made. In addition to the existing antibiotic and anti‐inflammatory topical eye therapy, systemic treatment with minocycline 50 mg twice a day was started. After marked improvement, the dose was reduced to 50 mg once a day. After further amelioration, treatment was switched to maintenance therapy with 40 mg of prolonged‐release doxycycline. Three years after a 12‐month course of anti‐inflammatory therapy, the patient remained recurrence free.     

Interventions for rosacea: abridged updated Cochrane systematic review including GRADE assessments

Rosacea is a common chronic facial dermatosis. This update of our Cochrane review on interventions for rosacea summarizes the evidence, including Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group assessments, of the effects of the currently available treatments. Searches included the following: Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS and the Science Citation Index, and ongoing trials registries (July 2014). We included 106 randomized controlled trials (RCTs) with 13 631 participants, a more than 80% increase since the last update in 2011. Pooling of data was feasible for a few outcomes, for topical metronidazole and azelaic acid and both appeared to be more effective than placebo (moderate and high‐quality evidence, respectively). Topical ivermectin was more effective than placebo based on two studies (high‐quality evidence), and slightly more effective than metronidazole in one study. Brimonidine was more effective than vehicle in reducing erythema in rosacea (high‐quality evidence). Ciclosporin ophthalmic emulsion was effective for ocular rosacea (low‐quality evidence). For oral treatments there was moderate‐quality evidence for the effectiveness of tetracycline based on two old studies, and high‐quality evidence for doxycycline 40 mg compared with placebo according to physician assessments. One study at high risk of bias demonstrated equivalent effectiveness for azithromycin and doxycycline 100 mg. Minocycline 45 mg may be effective for papulopustular rosacea (low‐quality evidence). Low‐dose isotretinoin appeared to be slightly more effective than doxycycline 50–100 mg (high‐quality evidence). Laser and light‐based therapies for erythema in rosacea were effective (low‐quality evidence). Further RCTs are required for ocular rosacea.     

A case of Scalp Rosacea treated with low dose doxycycline and probiotic therapy and literature review on therapeutic options

Rosacea is a common chronic inflammatory disorder showing a wide range of clinical features such as telangiectasia, erythema, papules, and pustules primarily involving the central part of face (forehead, cheeks and nose) although extra facial manifestation have been described. We describe a case of rosacea with predominant scalp involvement successfully treated with a 8‐week‐course of doxycycline 40 mg once a day and probiotic therapy twice a day (Bifidobacterium breve BR03, Lactobacillus salivarius LS01 1 × 10⁹ UFC/dose).     

Doxycycline 40 mg Capsules (30 mg Immediate-Release/10 mg Delayed-Release Beads)

Anti-inflammatory dose doxycycline 40 mg capsules (30 mg immediate-release and 10 mg delayed-release beads) provide a sub-antimicrobial dose that reduces the inflammatory response in patients with rosacea without producing drug concentrations required to treat bacterial diseases. The efficacy of oral, anti-inflammatory dose doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two pivotal large, randomized, double-blind, placebo-controlled, multicenter trials. After 16 weeks’ therapy, anti-inflammatory dose doxycycline 40 mg was significantly more effective in improving rosacea than placebo, providing a greater reduction in the total inflammatory lesion count (primary endpoint) than placebo. Anti-inflammatory dose doxycycline 40 mg was associated with a rapid onset of action, achieving a significantly greater decrease in total inflammatory lesion count than placebo by the first follow-up visit at week 3 in both studies. Maximum anti-inflammatory efficacy appears to be achieved with doxycycline 40 mg capsules once daily, as no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily (usual antibacterial dosage) in a small, randomized, double-blind trial. Anti-inflammatory dose doxycycline 40 mg was generally well tolerated in clinical trials, with most adverse events being of mild to moderate intensity.     

Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments

Rosacea is a common, chronic skin condition causing flushing, redness, red pimples and pus-filled spots (pustules) on the face. It affects about 1-20% of people worldwide. Rosacea can also cause inflammation of the eyes/eyelids (ocular rosacea) and thickening of the skin, especially the nose (rhinophyma). Although the cause of rosacea is unclear, treatments are available for this distressing disease. This review from the Netherlands, U.K. and Canada aimed to find out which treatments are effective for rosacea. The authors included data from 152 studies. For reducing redness, brimonidine and oxymetazoline worked from three up to 12 hours after being applied. For reducing pimples and pustules with topical (applied to the skin) treatments, azelaic acid, ivermectin and metronidazole were effective and safe. Ivermectin was slightly more effective than metronidazole. Minocycline foam also showed a large reduction in pimples and pustules. With oral (taken by mouth) antibiotics, tetracycline, doxycycline 40 mg or minocycline 45 mg reduced the number of pimples and pustules. Doxycycline 40 mg was likely as effective as 100 mg, with fewer side effects like diarrhoea and nausea. Oral minocycline 100 mg was as effective as doxycycline 40 mg. Azithromycin may be as effective as 100 mg doxycycline. Isotretinoin 0.25 mg/kg decreased pimples and pustules by 90%, and increased quality of life and patients’ satisfaction. Isotretinoin 0.3 mg/kg appeared to be slightly more effective than 50-100 mg doxycycline. However, isotretinoin is known to cause serious birth defects, so pregnancy must be avoided when using it. For treating dilated blood vessels, laser therapy and intense pulsed light therapy were both effective, but these studies had limited data. In ocular rosacea, ciclosporin 0.05% ophthalmic emulsion increased quality of life and improved the amount/quality of tears, and was slightly more effective than oral doxycycline. Omega-3 fatty acids likely improve dry eyes and tear gland function.     

Ocular signs, symptoms and tear function tests of papulopustular rosacea patients receiving azithromycin

Background  Tetracycline derivatives provide moderate benefit in the treatment of ocular rosacea. Recently, azithromycin has been found to be an effective alternative in the treatment of cutaneous papulopustular rosacea.
Objective  We planned a study to evaluate the effects of azithromycin on ocular symptoms, signs and tear function tests of papulopustular rosacea patients.
Methods  An open-labelled study was performed in a population of 20 papulopustular rosacea patients.
Results  Eighteen subjects completed the trial. Significant improvement was seen in ocular symptoms, eyelid findings and conjunctival hyperaemia scores ( P  = 0.002, P <  0.0001, and P  = 0.005, respectively). Therapeutic benefit was not observed in ocular surface staining scores. Baseline values of Schirmer test results were within normal limits. No significant side-effects were observed.
Limitations  The study population is limited to dermatology patients who had been referred to the ophthalmology clinic.
Conclusion  Azithromycin may be a new promising therapeutic alternative in ocular rosacea.

Conflicts of interest

None declared.     

Comparison of efficacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomized open clinical trial

Background Rosacea is a common inflammatory disorder of the skin. Systemic antibiotics currently used in the treatment of rosacea are sometimes associated with uncomfortable side effects. Therefore, a need for an effective agent with few side effects and good patient compliance exists. Azithromycin, a macrolide antibiotic with prolonged mode of action, has recently been found to be an effective alternative in the treatment of inflammatory acne. Methods For evaluation of the efficacy of azithromycin in the treatment of rosacea, we planned a randomized, open, clinical trial study to compare the efficacy of azithromycin with doxycycline in the treatment of this disease. Sixty‐seven patients were randomized to receive either azithromycin 500 mg thrice weekly (on Monday, Wednesday, and Saturday) in the first, 250 mg thrice weekly (on Monday, Wednesday, and Saturday) in the second, and 250 mg twice weekly (on Tuesday, and Saturday) in the third month. The other group was given doxycycline 100 mg/day for the three months. Clinical assessment was made at baseline, at the end of first, second, third, and 2 months after treatment. Side affects were recorded. The limitation of this study is that there was no blindness. Results Statistically significant improvement was obtained with both drugs. Neither drug was shown to be more effective than the other. In the azithromycin group four patients had diarrhea, while epigastric burning was seen in two patients using doxycycline. Conclusion This study indicates that azithromycin is at least as effective as doxycycline in the treatment of rosacea.     

The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities

Summary Background Rosacea has a major psychosocial impact on a patient’s life. Objectives To determine the impact of rosacea on patient quality of life, the relationship of quality of life scores to clinical and demographic variables, and the change in quality of life following various treatments. Methods Patients’ demographic and clinical characteristics were recorded at their initial examination and their response to treatment and side‐effects were recorded additionally at their follow‐up examination. Rosacea severity was scored for each of four signs from 0 to 3. Patients were requested to complete Dermatology Life Quality Index (DLQI) questionnaires. Results A total of 308 patients took part in this study. Mean ± SD DLQI total score at the initial visit was 6·93 ± 5·18 and was related to patients’ age, sex, age at disease onset, subjective symptoms, triggering factors, previous treatments, rosacea severity scores and patients’ self‐assessment of ease of living with rosacea. Of these 308 patients, 164 completed the DLQI following treatment. Mean ± SD post‐treatment DLQI score was 4·36 ± 4·82. Post‐treatment scores were also related to sex, type of treatment modality, development of side‐effects, improvement of rosacea, rosacea severity scores and patients’ self‐reported ease of living with rosacea. Topical metronidazole, oral tetracycline and oral isotretinoin were observed to reduce signs and symptoms of rosacea and DLQI scores significantly at this repeat examination. Conclusions Rosacea affects patients’ lives to a moderate extent, and this can be assessed by using DLQI. DLQI is also sensitive to quality of life changes brought about by treatment of rosacea. As a preliminary result we can say that topical metronidazole, oral tetracycline and oral isotretinoin seem to improve quality of life of patients by improving lesions of rosacea more efficiently than other therapeutic agents.     

Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review

Rosacea is a common chronic skin disease affecting the face. There are numerous treatment options, but it is unclear which are the most effective. The aim of this review was to assess the evidence for the efficacy and safety of treatments for rosacea. Searches included the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and Ongoing Trials Registers (updated February 2011). Randomized controlled trials in people with moderate to severe rosacea were included. Fifty-eight trials, including 27 from the original review, comprising 6633 participants were included in this updated review. Interventions included topical metronidazole, oral antibiotics, topical azelaic cream or gel, topical benzoyl peroxide and/or combined with topical antibiotics, sulphacetamide/sulphur, and others. There was some evidence that topical metronidazole and azelaic acid were more effective than placebo. Two trials indicated that doxycycline 40mg was more effective than placebo. There was no statistically significant difference in effectiveness between doxycycline 40mg and 100mg but there were fewer adverse effects. One study reported that ciclosporin ophthalmic emulsion was significantly more effective than artificial tears for treating ocular rosacea. Although the majority of included studies were assessed as being at high or unclear risk of bias, there was some evidence to support the effectiveness of topical metronidazole, azelaic acid and doxycycline (40mg) in the treatment of moderate to severe rosacea, and ciclosporin 0·05% ophthalmic emulsion for ocular rosacea. Further well-designed, adequately powered randomized controlled trials are required.     

A randomized, single-blind, placebo-controlled, split-face study with pimecrolimus cream 1% for papulopustular rosacea

Background Rosacea is a common inflammatory skin disorder for which the pathogenesis is unclear. Currently, there is no cure for rosacea, and it seems that standard therapies have focused mainly on minimizing inflammation. Objectives The aim of this study is to investigate the potential efficacy, tolerability and safety profile of 1% pimecrolimus cream for the treatment of rosacea. Methods Twenty‐five patients with papulopustular rosacea were enrolled to a randomized, single‐blinded, placebo‐controlled, split‐face trial of pimecrolimus cream 1% consisting 4 week treatment and 2 week follow‐up period. The patients were instructed to apply first the ‘left side cream’ labelled placebo cream (Ultrabase cream, Intendis GmbH, Berlin, Germany) to the left hemi‐face then the ‘right side cream’ labelled 1% pimecrolimus cream (Elidel; Novartis Pharma, Nuremberg, Germany) to the right hemi‐face, twice daily. They were informed to apply a standard amount of each cream with the fingertip‐unit and not allowed to use any other agent concomittantly other than sunblock. Clinical evaluation and subjective severity assessment were obtained along with photographic documentation at baseline, first, second, and fourth weeks of the therapy and at the follow‐up visit. Rosacea severity score for each sign of erythema, papules, pustules, oedema, and telengiectesia were graded from 0 to 3. Patients were questioned for the subjective symptoms, overall improvement on appearance and side‐effects. Results Twenty‐four patients completed the study with an exceptional compliance and tolerable safety profile. One patient withdrew from the study due to severe flare‐up reaction affecting both hemi‐faces. The mean baseline total rosacea severity scores were 5.06 + 1.29 for both sides and reduced to 2.5 ± 1.06 vs. 3.25 ± 1.24 on pimecrolimus vs. placebo applied sides without the significance (P = 0.06). There was not any significant difference concerning each rosacea sign scores and total rosacea severity scores except for the significant improvement in erythema score and total rosacea severity score obtained on the pimecrolimus‐applied hemi‐face at 2nd week of therapy (P =0.01 and P = 0.03, respectively). The reduction rates of the mean subjective severity scores at 4th week were 49.77% vs. 38.89% for pimecrolimus vs. placebo, respectively, without a statistical significance (P = 0.15). Subjective symptoms responded well in 54.16% of patients concerning pimecrolimus application compared with 12.50% for the placebo application. The side‐effects were mostly transient local irritations. Conclusion Our data implicated that pimecrolimus cream is not superior to placebo except for its efficacy on erythema. We believe that pimecrolimus cream can be a treatment option for rosacea patients with high erythema score for whom an initial accelerated improvement is needed. We believe further studies with topical pimecrolimus cream on larger study groups with different subtypes and severity of rosacea will clarify the potential effect of pimecrolimus cream for the treatment of rosacea.     

Four cases of Morbihan disease successfully treated with doxycycline

Morbihan disease (MD) is rosacea‐like disease characterized by persistent lymphedema on the upper half of the face. Currently, there is no established standard treatment for MD. Recently, MD has been reported to be associated with the infiltration of mast cells. The aim of this study was to investigate the association of treatment response and mast cell infiltration in MD. We report four cases of MD that were successfully treated with long‐term oral doxycycline therapy.     

Rosácea papulopustulosa: respuesta al tratamiento con azitromicina oral

Introduction

Oral tetracyclines and topical antibiotics have been used to treat papulopustular rosacea (PPR) for years, but it is not uncommon to find patients who do not respond to this standard treatment. In such refractory cases, oral azithromycin has proven to be an effective option.

2%夫西地酸乳膏联合小剂量盐酸米诺环素治疗玫瑰痤疮自身对照研究

目的:评价2%夫西地酸乳膏外用联合小剂量盐酸米诺环素口服治疗玫瑰痤疮的临床疗效。方法:选取门诊20例玫瑰痤疮患者,予盐酸米诺环素50 mg每晚口服,随机选择一侧面部外用2%夫西地酸乳膏,另外一侧作为对照,6周后评估临床疗效并测定皮肤红斑指数、经皮水分丢失和皮肤弹性,记录不良反应。结果:6周后外用夫西地酸侧总有效率和红斑指数分别为83.33%和982.94±8.09高于对照侧的22.22%和997.94±8.40(均P0.05);外用夫西地酸侧经皮水分丢失为16.17±3.79,低于对照侧的21.28±3.88(P0.05);治疗前后皮肤弹性无明显变化,组间无差异。结论:2%夫西地酸乳膏外用联合小剂量盐酸米诺环素口服治疗玫瑰痤疮较单用小剂量盐酸米诺环素口服更为有效。     

Potential association between rosacea and cancer: A study in a medical center in southern China

Growing evidence suggests that rosacea increases the risk of systemic diseases, but studies of the relationships between rosacea and cancer are rare. Aimed to assess the relationship between rosacea and cancer, a total of 7548 patients with confirmed internal malignancies and 8340 cancer‐free individuals aged 18 years or more were included in this study from November 2015 to October 2017. Clinical characteristics, personal history and laboratory data were recorded when patients were diagnosed with rosacea. Logistic regression analyses were performed to analyze associations between cancer and rosacea. We found rosacea significantly affected more women than men in both cancer and cancer‐free group. The data showed there was no relationship between rosacea and lung, gastrointestinal, nasopharyngeal and gynecological cancer. However, rosacea was significantly associated with the increased risk of breast cancer and glioma, but negatively associated with the risk of hematological cancer. Of the 190 female breast cancer patients with rosacea, 98.95% had the erythematotelangiectatic subtype of rosacea, 48.42% had chloasma and 76.31% of them were Fitzpatrick skin type III and IV. In our binary regression model, breast cancer patients with rosacea had a higher prevalence of estrogen receptor‐positive status, lower high‐density lipoprotein levels and higher low‐density lipoprotein than patients with breast cancer but no rosacea. Our findings indicate that rosacea is significantly associated with higher incidence of breast cancer, glioma and lower prevalence of hematological cancer.     

A case report of combination treatment with potassium-titanyl phosphate laser and brimonidine topical gel in erythematotelangiectatic rosacea

Laser therapies have been shown to provide symptom improvement in patients with erythema and telangiectasia of rosacea; however, they are associated with side effects such as erythema. Combinatorial treatment with pharmacological agents and laser have demonstrated better efficacy, fewer side effects and continued long-term remission compared with monotherapies. A case of moderate facial erythema that responded well to combination treatment with brimonidine 3 mg/g gel and a treatment course of potassium-titanyl phosphate (KTP) laser therapy is presented, showing a reduction from baseline, maintained after final laser session, by applying brimonidine 3 mg/g gel daily. Using brimonidine 3 mg/g gel to target post-laser treatment erythema is highly effective in minimising refractory erythema. Continued use of brimonidine 3 mg/g gel provides a sustained reduction of erythema, increasing the visibility of other signs and symptoms of rosacea that may be present. This can facilitate the treatment of these additional signs and symptoms.     

Therapeutic hotline: Successful treatment of Morbihan's disease with oral prednisolone and doxycycline

Persistent facial swelling can occur as a rare complication of rosacea. This finding is referred to as lymphedematous rosacea or Morbihan's disease. We report a case of a 45-year-old male with no previous history of rosacea who developed bilateral periorbital swelling associated with facial erythema and edema that responded to a combination of oral corticosteroids and doxycycline. Biopsy revealed changes of granulomatous rosacea.