Acne Vulgaris

Mild to moderate acne vulgaris: An overview of current therapy, drug costs, quality of life, utility, pharmacoeconomic and effectiveness of Duac®, Epiduo® and Zineryt® studies conducted.Preparatory work for a pharmacoeconomic study on acne vulgaris.

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit. Its symptoms are open and closed comedones, inflammatory papules, pustules, cysts and nodules that are mainly located on the face or upper trunk. Excessive sebum production is also a feature. The inflammatory lesions often result in scars.1 The clinical spectrum of acne ranges from mild manifestations with a few comedones to severe inflammation with abscess formation.2 The disease probably results from different interacting pathogenetic factors: microbial inflammation with propionibacterium acnes, seborrhea, follicular hyperkeratosis and inflammatory processes.2

Acne is one of the three most prevalent skin diseases in the general population and exists in different ethnicities including Caucasians, Asians, Indians and African Americans.1 It effects almost everyone between the age of 15 and 17 years. A study from the U.S. found a prevalence rate of 85% in U.S.-citizens aged 12-24 years.1 Others showed the high prevalence of acne in adults, ranging from 50,9% in women aged 20-29 to 15,3% for women aged 50 years and older.3

While acne vulgaris is not a life threatening disease, it seriously affects the quality of life of patients. Mittmann et al. and Klassen et al. reported an utility score of 0,84 (HUI-Mark III and EQ-5D).4,5 The severity of the acne correlates with the impact on the quality of life of the patients. Patients with severe acne experience greater psychosocial and emotional impairment than patients with a milder form of acne.6

This overview is made in preparation for a future pharmacoeconomic study on the treatment of mild to moderate acne and will cover:

The current pharmacotherapeutic treatment of acne vulgaris in The Netherlands and the United Kingdom. The evidence on the effectiveness and the costs of Duac®, Epiduo® and Zineryt®. An overview of the studies found on the utility and quality of life for patients with acne vulgaris. An overview of the pharmacoeconomic studies found on the treatment of acne vulgaris.

1. Current pharmacotherapeutic treatmentTo get a good view on the different pharmaceutical interventions used to treat acne, the treatments of two countries were compared; the United Kingdom and the Netherlands. It turned out the drugs and the clinical practice guidelines used in both countries are strongly comparable with just a few minor differences.

1.1 Drug classes used in the treatment of acne vulgarisAcne is caused by several pathogenic factors, as stated in the introduction. The classes of drugs used in the treatment of acne often focus on one or a few of these factors. By combining different drug classes, the different acne symptoms and causes can be addressed. The classes of drugs used in the treatment of acne vulgaris in the United Kingdom and the Netherlands are:

Benzoyl peroxideBenzoyl peroxide diminishes papules and pustules due to the antibacterial effect against the anaerobe Propionibacterium acnes, probably due to the slow release of oxygen. It also has a mild keratolytic function by oxidation of the disulfide bridges in keratine. This has a negative effect on the formation of comedones. Benzoyl peroxide also has a sebostatic effect, it suppresses excessive sebum production, thus causing dry skin.7,8

Topical retinoidsRetinoids are vitamin A derivatives and are comedolytic due to their effect on the desquamation of the follicular epithelium. They also work anti-inflammatory. Tretinoin and adapalene are the two most used topical retinoids. There is no difference in effectivity between the two, adapalene possibly has less serious side-effects. Topical retinoids are contraindicated during pregnancy and lactation.8,9

Topical antibioticsTopical antibiotics have an anti-inflammatory and an antibacterial effect. Erythromycin and clindamycin are most commonly used. A combination treatment of benzoyl peroxide or a topical retinoid with a topical antibiotic is more effective than just a topical antibiotic and reduces the chance of bacterial resistance to the antibiotic.8,9

Oral antibioticsOral antibiotics (ex. tetracycline, doxycycline, minocycline, erythromycin, trimethoprim/sulfamethoxazole, trimethoprim and azithromycin) repress the Propionibacterium acnes and have immunomodulatory and anti-inflammatory effects. There hasn’t been found any difference in effectivity between the oral antibiotics. The choice between a topical and an oral antibiotic is arbitrary and depends on the preference of the patient, compliance, failure of other therapies, other drugs used by the patient and comorbidity.8,9

Oral retinoidsIsotretinoin is the only oral retinoid used and is used mostly for the treatment of severe acne. It slows the secretion of sebum, has a keratolytic effect, reduces the growth of Propionibacterium acnes, works anti-inflammatory and has a normalizing effect on the desquamation of the epithelium. Isotretinoin is a strong teratogen and has a long list of other mostly dose-dependent and reversible side effects.7-9

Oral anticonceptivesOral anticonceptives can be used to treat women with acne that also want to prevent pregnancy. It has a positive effect on both inflammatory and non-inflammatory acne lesions. Effects only start to show after 3 to 6 months of use.8,9

Azelaic acidAzelaic acid is a saturated dicarboxylic acid. It has a keratolytic effect and a bacteriostatic effect against Propionibacterium acne. It causes less skin irritation than topical retinoids or benzoyl peroxide. It is a second-line option in the United Kingdom, but it is not in the standard treatment regimens for acne in The Netherlands.7,10

1.2 Clinical practice guidelinesTable 1 shows three different guidelines for the treatment of acne vulgaris. The ‘NHG-standaard’ is the standard guideline for Dutch general practitioners, the ‘Groninger Formularium’ contains guidelines for medical professionals in the region of the Dutch province Groningen.8,11 The ‘National Institute for Health and Care Excellence’ is an institute that provides national guidance to improve health and social care in the United Kingdom. This guideline is from their ‘Clinical Knowledge Summaries’.10 The steps-format in the first column is adopted from the ‘NHG-standaard’. The other two guidelines don’t officially use these steps, but were freely transformed to this format for easy comparison between the guidelines.

The guidelines all start with a topical treatment with a single drug and later combine it with another topical drug. These can be benzoyl peroxide, topical retinoids or topical antibiotics. Oral antibiotics are added when the topical treatment isn’t sufficient. A difference between the Dutch and the British guidelines is the use of azelaic acid as an alternative to benzoyl peroxide or a topical retinoid in the British guidelines. Another difference is that the Dutch guidelines add an oral retinoid: isotretinoin as a final solution, the British guideline doesn’t.

Table 1: Three different clinical practice guidelines for the treatment of acne vulgaris.

Steps in treatment

NHG-Standaard8 Groninger Formularium 201111 NICE - CKS10

Step 1a Benzoyl peroxide or a topical retinoid.

Benzoyl peroxide Benzoyl peroxide or a topical antibiotic

Step 1b Exchange the benzoyl peroxide or the topical retinoid for the other.

Add a topical retinoid Exchange with a topical retinoid or with azelaic acid

Step 2a Add a topical antibiotic. Combine a topical antibiotic with benzoyl peroxide or a topical retinoid

Combine a topical antibiotic with benzoyl peroxide

Step 2b If you didn’t in step 1b: Exchange the benzoyl peroxide or the topical retinoid for the other.

Combine a topical antibiotic with a topical retinoid or a topical retinoid with benzoyl peroxide

Step 3 Exchange the topical antibiotic for an oral antibiotic (first choice: doxycycline)

Exchange the topical antibiotic for an oral antibiotic

Exchange the topical antibiotic for an oral antibiotic

Step 4 Isotretinoin Isotretinoin

Facultative Oral anticonceptive Oral anticonceptive Oral anticonceptive

2. Effectiveness and costs of Duac®, Epiduo® and Zineryt®2.1 MethodsFor the comparison of the drug costs the official prices of the drugs in the Dutch reimbursement system were used, which can be found on http://www.medicijnkosten.nl. The drug prices get updated every month, the prices used were the prices in july 2013.12

In order to make a complete overview of the current English literature available on the effectiveness of Duac®, Epiduo® and Zineryt® in the treatment of acne, not only studies on the proprietary drugs but studies on formulations of the same active ingredients were also included in the table. A PubMed search was performed using permutations and different combinations of the keywords Duac®, Epiduo®, Zineryt®, Acne, Clindamycin, benzoyl-peroxide, adapalene and erythromycin. A full list of all the PubMed searches executed is included in appendix I . Some articles found couldn’t be accessed with the current licenses from the University of Groningen. These studies are not included in this overview.

2.1 Results: EffectivenessTables 2, 3 and 4 show the studies found on the effectiveness of clindamycin phosphate 1%/benzoyl peroxide 5% gel (Duac®, CL/BPO), adapalene 0,1%/benzoyl peroxide 2,5% gel (Epiduo®, ADA/BPO) and topical erythromycin 4%/zinc 1,2% (Zineryt®, ERY/Z). In total 12 studies were found; 4 on CL/BPO, 3 on ADA/BPO, 3 on ERY/Z and 2 others. The study of Langner et al. included both CL/BPO and ERY/Z and is included in table 2.13 Tunca et al. did not study ERY/Z but an erythromycin 4% gel without zinc, the study is however included in table 5 to be able to compare its effect to ERY/Z.14

The studies on CL/BPO and ADA/BPO have been published more recently than the studies on ERY/Z. This is to be expected since Zineryt® already got approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 1990. Epiduo® and Duac® are newer drugs, just approved in 2009 and 2013 respectively.15

When available from the article the mean or median percentage change in total, inflammatory and non-inflammatory lesion count were noted in the ‘key results’ column. This makes a rough comparison between the studies possible.

When looking at the reduction in lesion count CL/BPO, ADA/BPO and ERY/Z all seem effective.

CL/BPO and ADA/BPO work differently in that CL/BPO has a topical antibiotic and ADA/BPO a topical retinoid, but their effectiveness doesn’t show huge differences.

ERY/Z scores far lower on the non-inflammatory lesion reduction than on the inflammatory lesion reduction. A logical explanation would be that erythromycin is an antibiotic and thus only helps against the lesions caused by inflammation with p. acnes.

In the studies that were placebo-controlled it is shown that there is a placebo-effect, but the combination gels and the ERY/Z are significantly more effective.

The studies that compared the combination gels with monotherapies all found the combination gels to be significantly more effective.

None of the studies showed serious adverse events that were related to the drugs used. The most common adverse event in all the therapies was dry skin, but in most subjects this wasn’t a reason to stop the therapy.

2.2 Results: Treatment regimens and costs

Table 5 shows treatment regimens for CL/BPO, ADA/BPO, ERY/Z and the separate drugs adapalene (ADA), benzoyl peroxide (BPO), clindamycin (CL), erythromycin (ERY) obtained from 4 sources: the NHG-standaard (NHG), the Groninger Formularium (GF), the National Institute for Care Excellence (NICE) and the Farmacotherapeutisch Kompas{{112 College voor Zorgverzekeringen}} (FK). The first three got explained in part 1.2, the latter is the official Dutch source for information on medicines and can be compared with the British National Formulary.

Most of the recommendations differ between the sources, except for ADA and BPO. Those treatment regimens seem to have become more or less standardized over all guidelines.

Epiduo and Duac are not found in the guidelines, probably because they are to new. Zineryt is not in the Dutch guidelines but is in the British one.

Prolonged use of antibiotics, erythromycin and clindamycin, is discouraged in all the guidelines to reduce the chance for resistant bacteria. A noteworthy difference is that the British guideline states a maximum usage of 6-8 weeks, while the Dutch NHG-standaard allows a maximum usage of 3-6 months.

Table 6 shows the drug costs for CL/BPO, ADA/BPO, ERY/Z and ADA, BPO, CL, ERY in the Netherlands. Duac is the most expensive (€0,55 per gram) of the three treatments being compared in this overview and Zineryt (€0,34 per gram) is the cheapest. Epiduo costs €0,46 per gram.

Simply adding the costs of the two separate drugs, shows that it's cheaper to buy both the separate gels than to buy the combination gels. €0,33 Per gram instead of 0,46 per gram for ADA+BPO and €0,18 per gram instead of €0,55 per gram for BPO+CL. This should be taken in to account when conducting a cost-effectiveness study on the combination therapies. Note that it could be possible that combining two separate gels won't give the same results as the combination gels would give.

3. Utility and quality of life3.1 MethodsIn order to make an overview of all the English utility and quality of life data on acne, a PubMed literature search was performed. The keywords used included permutations and different combinations of acne, EQ-5D, utility, time-trade-off, health preferences, health outcome, standard gamble and quality of life. Some articles found couldn’t be accessed with the current licenses from the University of Groningen. These studies are not included in this overview.

3.2 Results: Utility studies3.3 Results: Quality of life studies4. Pharmacoeconomic studies4.1 Methods4.2 Results5. Conclusion -> Chronic disease, relapse rates6. References7. Appendix

Table 2: An overview of effectiveness studies on Clindamycin phosphate 1%/benzoyl peroxide 5% gel (Duac®)Study, year and country Patient population Treatments compared; method Outcome measure Key results

Cunliffe et al., A Randomized, Double-Blind Comparison of a Clindamycin Phosphate/Benzoyl Peroxide Gel Formulation and a Matching Clindamycin Gel with Respect to Microbiologic Activity and Clinical Efficacy in the Topical Treatment of Acne Vulgaris, 200216

United Kingdom

13 To 30 years of age with mild to moderate acne: Propionibacterium acnes counts >104 CFU per cm2 of skin and 15 to 100 inflammatory lesions, 15 to 100 comedones, and <2 nodules/cysts on the face.

N=70

Clindamycin phosphate 1%/benzoyl peroxide 5% gel (twice daily, 16 weeks) compared with clindamycin 1% /placebo gel (twice daily, 16 weeks)

Single-center, double-blind, randomized, parallel-group study

Facial lesion counts, Physician's Clinical Global Improvement (CGI) score, counts of total and clindamycin-resistant facial P acnes and coagulase-negativeStaphylococci, adverse-events.

The total P acnes count and the clindamycin-resistant P acnes count were significantly reduced after 16 weeks of treatment with combination gel compared with clindamycin monotherapy. These reductions in total P acnes and clindamycinresistant P acnes counts correlated with reductions in total acne lesions.

Mean % change in total lesion count: week 12; week 16: combination gel: -59,1; -52,7. Clindamycin: -33,1; -27,5.

Langner et al., A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide (Duac®) and erythromycin + zinc acetate (Zineryt®) in the treatment of mild to moderate facial acne vulgaris, 200713

Poland and United Kingdom

Male and female patients aged 12–39 years with mild to moderate acne vulgaris of the face, with at least 15 inflammatory and/or non-inflammatory lesions but nomore than three nodulocystic lesions and an acne grade of less than 7.

N=148

Clindamycin 1% / benzoyl peroxide 5% (Duac®) gel (once daily, 12 weeks) compared with erythromycin 4% / zinc acetate 1,2% (Zineryt®) (twice daily, 12 weeks)

Multicenter, randomized, single-blind, parallel-group study

Inflammatory and noninflammatory lesion count, global improvement and adverse events.

CDP + BPO showed an earlier onset of action with a faster significant reduction in total lesion counts than ERY + Zn.

Reductions in the total lesion count at endpoint of 69,8% for CDP + BPO group and 64,5% for ERY + Zn group. Both treatments were well tolerated.

Ko et al., Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerability, 200917

South Korea

Subjects age 12 years and older with acne vulgaris of mild to moderate severity: >12 inflammatory lesions, <4 nodules or cysts, >12 non-inflammatory lesions, an acne grade of ≥ 2.0 and < 7.0 as in Leeds revised acne grading system and ≥ 2.0 and < 4 as in KAGS-2.

N=69

Clindamycin phosphate l%/benzoyl peroxide 5% gel (once daily, 12 weeks) compared with adapalene 0,1% gel (once daily, 12 weeks)

Prospective, randomized, open-label

Efficacy was assessed by lesion counts, acne grading system and global improvement.

Adverse events were alsoevaluated in scale of 0 (none) to 3 (severe).

Both CDP/BPO and ADA were effective in reducing lesion counts and acne severity scale and showedsignificant global improvement. However, CDP/BPO offered greater efficacy against inflammatory lesions than ADA.

Both drugs were well tolerated with minimal adverse drug reactions.

(Percentages of change in lesion counts are in graphs in the publication.)

Green et al., Efficacy and Tolerability of a Three-Step Acne System Containing a SolubilizedBenzoyl Peroxide Lotion versus a Benzoyl Peroxide/Clindamycin Combination Product. An Investigator-Blind, Randomized, Parallel-Group Study, 200818

United States of America

Subjects age 12 to 45 years with acne vulgaris of mild to moderate severity who also had normal-to-dry skin:10–100 Non-inflammatory lesions (open comedones + closed comedones), 17–40 inflammatory lesions (papules + pustules +nodules), up to two nodulocystic lesions.

N=21

Solubilized 5% benzoyl peroxide lotion + proprietary cream cleanser and moisturizer (once daily, 4 weeks) compared with Clindamycin phosphate l%/benzoyl peroxide 5% gel (once daily, 4 weeks)

Single-center, Investigator-Blind, Randomized, Parallel-Group Study

- Non-inflammatory lesion count reduction- Inflammatory lesion count reduction- Erythema, dryness, peeling, burning/stinging, itching- Patient rating of effectiveness of treatment- Patient rating of acne improvement- Patient satisfaction with acne improvement- Adverse events

Both reduced comedo count by a mean of 38%-48%, and reduced inflammatory lesion count by a mean of 63%-66%.

The three-step acne system group achieved arelatively greater mean improvementin satisfaction score.

They scored the same for dryness and peeling and the BPO/clindamycin scored better on the burning/stinging score.

Seidler et al., Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, andcombination benzoyl peroxide/clindamycin in acne, 201019


A total of 23 studies including 7309 patients were used in the meta-analysis.

5% Benzoyl peroxide (BPO),1% to 1,2% clindamycin (CL), 5% BPO with 2% salicylic acid (SA), and available combinations of BPO/CL (5% BPO/1% CL and 2,5% BPO/1,2% CL) (2 to 4 weeks and/or 10 to 12 weeks)

Meta-analysis in accordance with PRISMA from the Cochrane collaboration guidelines.

Inflammatory and noninflammatory lesion reduction and/or percent lesion reduction

At early time points, 5% BPO 1 SA had the best profile. BPO/CL was only incrementally better than BPO alone but was superior to CL alone. At later time points, 5% BPO 1 SA was similar to BPO/CL.

2-4 weeks:Mean % change in lesion count: inflammatory; noninflammatory: BPO: -33,4; -19,1. CL: -21,5; -10,0. BPO + SA: -55,2; -42,7. BPO/CL: -40,7; -26,2. Placebo: -7,3; -6,7.

10-12 weeks:Mean % change in lesion count: inflammatory; noninflammatory: BPO: -43,7; -30,9. CL: -45,9; -32,6. BPO + SA: -51,8; -47,8. BPO/CL: -55,6; -40,3. Placebo: -26,8; -17,0.

Table 3: An overview of effectiveness studies on Adapalene 0,1%/benzoyl peroxide 2,5% gel (Epiduo®)

Study, year and country Patient population Treatments compared; method Outcome measure Key results

Thiboutot et al., Adapalene-benzoyl peroxide, a fixed-dosecombination for the treatment of acne vulgaris: Results of a multicenter, randomized double-blind, controlled study, 200720


Male and female subjects, 12 years of age or older, with 30 to 100 noninflammatory facial lesions, 20 to 50 inflammatory facial lesions, and no nodules or cysts.

N=517

Adapalene 0,1% / benzoyl peroxide 2,5% gel compared with adapalene 0,1% gel, benzoyl peroxide 2,5% gel and the gel vehicle (all once daily for 12 weeks)

Randomized, multicenter, double-blind, parallel group study

Success rate (subjects ‘‘clear’’ or ‘‘almost clear’’), lesion count, cutaneous tolerability and adverse events.

The fixed-dose combination gel of adapalene and BPO was significantly more effective than corresponding monotherapies, with significant differences in total lesion counts.

Median % change in lesion count: Total; inflammatory; noninflammatory: Adapalene-BPO -51,0; -62,9; -51,2. Adapalene: -35,4; -45,7; -33,3. BPO: -35,6; -43,6; -36,4. Vehicle: -31,0; -37,8; -37,5.

Gollnick et al., Adapalene–benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients, 200921

U.S.A., Canada, Europe

Enrolled subjects were male or female of any race, 12 years of age or older with acne vulgaris, having on the face 20–50 inflammatory lesions, 30–100 noninflammatory lesions and anInvestigator’s Global Assessment (IGA) score of 3, corresponding to moderate acne. Patients were to have no morethan one active nodule at baseline.

N=1670


Randomized, multicenter, double-blind, active- and vehicle-controlled parallel group study

Evaluations included success rate (subjects ‘clear’ or ‘almost clear’), percentage change in lesion count from baseline, cutaneous tolerability and adverse events.

Adapalene–BPO was significantly more effective than corresponding monotherapies, with significant differences in percentage lesion count change observed as early as 1 week. Cutaneous tolerability profile was similar to adapalene. Adverse events were more frequent with the combination therapy (mainly due to an increase in mild-to-moderate dry skin)

Median % change in lesion count: Total; inflammatory; noninflammatory: Adapalene-BPO -65,4; -70,3; -62,2. Adapalene: -52,3; -57,1; -50,4. BPO: -48,2; -61,9; -48,8. Vehicle: -37,1; -45,5; -36,7.

Tan et al., Synergistic efficacy of adapalene 0.1%-benzoyl peroxide 2.5% in the treatment of 3855 acne vulgaris patients, 201122

U.S.A, Puerto Rico, Canada, Germany, Polandand Hungary

Eligible patients were 12 years or older with 20–50 inflammatory lesions, 30–100 non-inflammatory lesions, no cysts and no more than one nodule on the face.

N=3855


Pooled analysis from three double-blind, randomized, controlled studies (Thiboutot 2007, Stein Gold 2009, Gollnick 2009)

Percent reduction in lesion counts, Investigator’s Global Assessment (IGA) success and adverse events.

Adapalene-BPO combination gel provides synergistic and significantly greater efficacy than its monotherapies in the treatment of acne vulgaris.

Median % change in lesion count: Total; inflammatory; noninflammatory: Adapalene-BPO: -59; -66; -58. (Other percentages are in graphs in the publication.)

Table 4: An overview of effectiveness studies on topical erythromycin 4%/zinc 1,2% solution (Zineryt®)

Study, year and country Patient population Treatments compared; method Outcome measure Key results

Feucht et al. Topical erythromycin with zinc in acne: A double-blind Controlled study, 198023


Patients were male students at the University of Georgia and were between the ages of 18 and 26.

N=141

Erythromycin 4% / 1,2% zinc acetate liquid compared with Erythomycin 4% / 1,2% zinc octoate, 250 mg oral tetracycline and placebo. (all twice daily for 10 weeks)

Double-blind, randomized, vehicle-controlled, parallel-group study

Severity grade, papule counts, pustule counts, comedo grades, and comedo counts.

Erythromycin/zinc liquid and gel were significantly better than placebo and as effective as the oral tetracycline. Analysis of comedo grades showed that at weeks 8 and 10 the 4% topical erythromycin/zinc liquid showed a reduction statistically better than placebo.

% Change in lesion count: papules (inflammatory); comedones (noninflammatory): Erythromycin/zinc liquid: -58,11; -14,83. Erythromycin/zinc gel: -44,65;*. Oral tetracycline: -51,17;*. Placebo: -25,43; 14,09.

Pustule counts showed no statistically significant difference between groups throughout the study.

*not mentioned in the publication.Schachner et al., Topical erythromycin and zinc therapy for acne, 199024


Female subjects, between 13 and 36 years of age, with a Cook acne grade of at least 3 (scale from 0-8, 8 being severe acne).

N=57 (39 for the full year)

Erythromycin 4% / 1,2% zinc acetate compared with its vehicle (twice daily for 12 weeks). The study continued for 40 weeks after the first 12 weeks, but all subjects were treated with Erythromycin 4% / 1,2% zinc acetate during this period.

Double-blind, randomized, vehicle-controlled, parallel-group study (for the first 12 weeks)

Acne severity grades, papule, pustule, comedo, total inflammatory lesion count and adverse events.

In the first 12 weeks statistically significant differences were noted in the efficacy of theerythromycin-zinc compared with vehicle for acne severity grades (global assessment) andfor papule, pustule, and comedo counts. After crossover, the vehicle-treated group receivingactive therapy duplicated the improvement of the group initially treated with erythromycin/zinc.

(% Change in lesion count after 12 weeks: inflammatory; noninflammatory:Erythromycin 4% / 1,2% zinc acetate: -75; -64; vehicle: -50; -48.)*

*This is no actual data from the publication, the publication only mentions actual lesion counts in hard to read graphs. This is just an estimation of the % reduction for easy comparison.

Chu et al., The comparative efficacy of benzoyl peroxide 5%/erythromycin 3% gel and erythromycin 4%/zinc 1,2% solution in the treatment of acne vulgaris, 199725

United Kingdom and U.S.A.

Ages 13-39 years, with grade II or III acne (Pillsbury classification), having from 10 to 62 inflammatory lesions and from 18 to 120 comedones on the face and forehead.

N=72

Benzoyl peroxide 5% / erythromycin 3% gelcompared with erythromycin 4%/zinc 1,2% solution. (both twice daily for 10 weeks)

Evaluator-blinded, randomized, parallel-group study

Acne grade, number of lesions, scores for facial oiliness, erythema and peeling, global improvement score, cosmetic acceptability, physician, patient global evaluations and adverse events.

Benzoyl peroxide 5% /erythromycin 3% gel was significantly better on all outcome measures.

Median % change in lesion count: inflammatory; noninflammatory: Benzoyl peroxide 5%/erythromycin 3%: -80*; -53. Erythromycin 4%/zinc 1,2%: -50*; -27.

*Are estimates from a graph in the publication.

Tunca et al., Topical nadifloxacin 1% cream vs. topical erythromycin 4% gel in the treatment of mild to moderate acne, 201014

Turkey

Subjects ranged in age from 18-28 years and had mild to moderate acne (acne grade ≥8 according to Leeds revised acne grading system).

N=86

Nadifloxacin 1% cream compared with erythromycin 4% gel* (both twice daily for 12 weeks)

Open label, randomized, parallel-group study

*Note this is not erythromycin 4%/ 1,2% zinc acetate.

Lesion counts, acne severity index (ASI: papules + (2 · pustules) + (0.25 · comedones)), global change of baseline and adverse events.

In both groups, there was a significant reduction in lesion counts and ASI scores beginning from the first visit at week 4.This reduction continued throughout the 12 week study period. Both treatments were well tolerated. The treatments are both safe and are equally effective.

Mean % change in lesion count after 12 weeks: Papules; pustules; comedones (noninflammatory); ASI: Nadifloxacin 1%: -48,58; -54,13; -22,48; -47,70. Erythromycin: -52,71; -57,14; -24,92; -50,97.

Table 5: Treatment regimens for CL/BPO, ADA/BPO, ERY/Z and ADA, BPO, CL, ERY.

Interventions Dosage Duration of treatment

NHG FK GF NICE SMC 2011*

NHG FK GF NICE

Adapalene gel (1mg/g) Once daily (irritable skin: once every two days)

Once daily Once daily (irritable skin: once every two days)

Once daily - Min. 6-8 weeks Min. 3-4 weeks Min. 6-8 weeks Min. 6 weeks

Benzoyl peroxide Hydrogel 5% (50mg/g)

Once or twice daily Once or twice daily


- Min. 6-8 weeks - Min. 3 months Min. 6 weeks

Benzoyl peroxide Hydrogel 10% (100mg/g)

- Once or twice daily


- - - Min. 3 months Min. 6 weeks

Clindamycin gel (10mg/g) Once daily Twice daily

Twice daily Once daily - Min. 6-8 wks, max. 3-6 months

At 4 weeks check for resistant bacterium

At 4 weeks check for resistant bacterium

Max. 6-8 weeks

Zineryt® (Erythromycin 4% + Zinc 1,2%)

- Twice daily

- Twice daily - - Min. 10-12 weeks - Max. 6-8 weeks

Erythromycin 1-2% gel or lotion Once daily Twice daily

- Twice daily - Min. 6-8 wks, max. 3-6 months

Min. 6 weeks - Max. 6-8 weeks

Epiduo® gel (0,1% adapalene + 2,5% benzoyl peroxide)

- - - - Once daily

- - - -

Duac® gel (50 mg benzoyl peroxide + 10 mg clindamycin/ g)

- Once daily - - - - Max. 12 weeks - -

*Source: Scottish Medicine Consortium 2011{{110 Scottish Medicines Consortium 2011}}

Table 6: Drug costs for CL/BPO, ADA/BPO, ERY/Z and ADA, BPO, CL, ERY.

Interventions Costs (incl. VAT) Costs of one week of treatment**

Amount reimbursed (NL)

Once daily Twice daily

Adapalene gel (1mg/g) € 0,23 per gram € 0,23 € 1,84 € 3,68Benzoyl peroxide Hydrogel 5% (50mg/g) € 0,10 per gram € 0,00 € 0,80 € 1,60Benzoyl peroxide Hydrogel 10% (100mg/g) € 0,13 per gram € 0,00 € 1,04 € 2,08Clindamycin gel (10mg/g) € 0,08 per gram € 0,08 € 0,64 € 1,28Zineryt® (Erythromycin 4% + Zinc 1,2%) € 0,34 per ml € 0,15 € 2,72 € 5,44Erythromycin 1-2% gel or lotion € 0,16 per gram € 0,16 € 1,28 € 2,56Epiduo® gel (0,1% adapalene + 2,5% benzoyl peroxide) * € 0,46 per gram - € 3,70 € 7,40Duac® gel (50 mg benzoyl peroxide + 10 mg clindamycin/g) € 0,55 per gram € 0,17 € 4,40 € 8,80*Source: Scottish Medicine Consortium 2011.{{110 Scottish Medicines Consortium 2011}}** Used 16g as the amount of gel needed to smear the head and the neck twice daily for a week, source: Farmacotherapeutisch Kompas.{{106 College voor Zorgverzekeringen}}

Table 7: An overview of utility studies regarding acne vulgaris.

Study, year and country Patient population Objectives of evaluation Details of methods Utility results

Mittmann et al., Utility Scores for Chronic Conditions in a Community-Dwelling Population, 19994

Canada

Patients with acne vulgaris requiring medication, 12 years of age and older.

N=476

To determine utility scores for various chronic conditions.

Source of utilities:A questionnaire, the National Population Health Survey, held among 17.626 Canadians. Health status was converted to utility according to the Health Utilities Index-Mark III (HUI-Mark III).

Utilities of relevance cover:- Utility for acne that requires medication*- Utility for acne that requires medication in men*- Utility for acne that requires medication in women*- Utility for acne that requires medication and no comorbidities- Utility for acne in subjects age: 12 – 19- Utility for acne in subjects age: 20 – 29*comorbidities possible

HUI-Mark III:

Mean (SD) utility for:Acne that requires medication and no comorbidities: 0,94 (0,063)Acne that requires medication: 0,92 (0,089)Acne that requires medication in men: 0,93 (0,077)Acne that requires medication in women: 0,90 (0,095)Acne in subjects age: 12-19: 0,92 (0,90) (N=85)Acne in subjets age: 20-29: 0,92 (0,087) (N=48)

Klassen et al., Measuring quality of life in people referred for specialist care of acne: Comparing generic and disease-specific measures, 20005

United Kingdom

Patients with acne vulgaris in any form, between 16 and 39 years of age.

N=54

Compare 3 approaches (EQ-5D, SF-36, Dermatology Life Quality Index) to the measurement of quality of life in patients referred for specialist care of acne.

Source of utilities:Sent the 3 questionnaires to 130 subjects before treatment (returned by 111) and 2 follow-ups: at 4 months (N=61) and at 12 months (N=60) after treatment began.

Utilities of relevance cover:EQ-5D score, EQ-5D VAS, SF-36 PCS, SF-36 MCS and DLQI of subjects with acne:- Before treatment- After 4 months of treatment- After 12 months of treatment

EQ-5D:

Mean (SD) utility for:Before treatment: 0,82 (0,16) (N=56) / 0,84 (0,17) (N=54)After 4 months of treatment: 0,89 (0,17)After 12 months of treatment: 0,93 (0,15)

Chen et al., A Catalog of Dermatology Utilities: A Measure of the Burden of Skin Diseases, 200427


Patients with acne vulgaris, acne rosacea or milia.

N=30

To introduce the concept of utilities to the dermatology community and to present a catalog of dermatology utilities obtained from direct patient interviews.

Source of utilities:Interview with 30 patients.

Utilities of relevance cover:Instruments: TTO- Utility for patients with acneiform eruptions.

TTO:Mean utility: 0,940 (SD: 0,120)Median utility: 0,990

Chen et al., A Community-Based Study of Acne-Related Health Preferences in Adolescents, 200828


Volunteer sample of adolescents, aged 14-18 years, with a score of 1 or higher on theInvestigator’s Static Global Assessment (ISGA) scale for acne.

N=266

To examine preferences for acne-related outcomes in adolescents.

Source of utilities:A self-administered written survey.

Utilities of relevance cover:Instruments: TTO and willingness to pay.- Utility for current acne state3 Hypothetical acne-related states:- 100% clearance- 50% clearance- 100% clearance but with residual scarring

TTO:Mean (SD) [Median] utility for:Current acne state: 0,961 (0,092) [0,985]100% Clearance: 0,978 (0,073) [0,994]50% Clearance: 0,967 (0,089) [0,992]100% Clearance with scarring: 0,965 (0,091) [0,992]

Willingness to pay: $275 to never had acne in their lifetime and significantly more for 100% clearance than for 50% clearance or 100% clearance with scarring.

Table 8: An overview of quality of life studies regarding acne vulgaris

Study, year and country Patient population Objectives of evaluation Details of methods Results

Mosam et al., Quality of life issues for South Africans with acne vulgaris, 200529

South Africa

Patients aged 12 to 47 years, with mild to severe acne.

N=107

To study the adverse effects of acne on the psyche in predominantly black patients.

Source of scores:- General Health Questionnaire (GHQ)- Dermatology Specific Quality of Life Questionnaire (DSQL)- Grading of the acne by the Global Acne Grading scale (GAG).

Scores of relevance cover:- DSQL scores for patients with acne with different severities according to the GHQ.

GHQ:45,8% ND (no distress), 20,6% PD (psychological distress), 33,6% SPD (severe PD).Mild acne: 53,1% PD, moderate acne: 57,1% PD, severe acne: 62,5% PD.There was no association between clinical severity and PD.

DSQL:Distress level: physical symptoms; activities of daily living; overall mental health; social activities; work/school activities; feelings (median values).Mild: 12,00; 5,00; 9,00; 7,50 ;0; 10,50Moderate: 12,00; 7,00; 10,00; 10,00; 2,00; 13,00Severe: 15,00; 9,00; 13,50; 18,00; 5,00; 16,00P-value: 0,079; 0,033; <0,0001; 0,0168; 0,0032; 0,0002

Ozolins et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne, 200530

United Kingdom

Patients with mild to moderate inflammatory acne, aged 12 to 39 years.

N=649

To determine the relative efficacy and cost-effectiveness of five of the most commonly used antimicrobial preparations for treating mild to moderate facial acne in the community

Source of scores:- SF36- CDLQI- DLQI- Dermatology Quality of Life Scales (DQOL)- Willingness to Pay (WTP)- Willingness to Accept (WTA)

Scores of relevance cover:All at 0, 6, 12, 18 weeks of treatment:- SF-36 scores by gender, age, intervention.- DLQI and CDLQI scores by intervention.- DQOL scores by intervention.- WTP and WTA amounts per intervention.

Mean DLQI | CDLQI scores at 0 weeks of treatment: Oxytetracycline; minocycline; benzoyl peroxide, Erythromycin + BP twice daily; Erythromycin + BP once daily: 5,4; 4,6; 4,5; 4,9; 5,2 | 3,7; 3,9; 4,7; 4,5; 3,2.

The median amount a participant would pay for an almost certain cure at week 0: 4 groups: £25, 1 group: £50.

The median amount of money a participant would take instead of the treatment: 4 groups: £500, 1 group: £1000.

All other scores and amounts are in table 21 and the tables 97 to 126 of the publication.

Walker et al., Quality of life and acne in Scottish adolescent schoolchildren: use of the Children’s Dermatology Life Quality Index© (CDLQI) and the Cardiff Acne Disability Index© (CADI), 200631

United Kingdom (Scotland)

Subjects aged 15-18 years, with and without acne.

N=147*

*The publication mentions 147 subjects completely filled in the questionnaires and were used in the data analysis and also mentions 147 subjects had acne. But it’s not clear if all the 147 subjects used in the analysis had acne.

Measurement of the impairment of health-related quality of life (HRQoL) in teenage Scottish schoolchildren in a comparative study using two HRQoL questionnaires.

Source of scores:- Cardiff Acne Disability Index (CADI)- Children’s Dermatology Life Quality Index (CDLQI)

Scores of relevance cover:- CADI and CDLQI score*

Mean CDLQI; CADI score:1.7; 1.9

Although the overall mean total CLDQI and CADI scores were low, an important 11% of pupils scored highly across both questionnaires, 8% moderately and 3% severely.

There was no significant difference in mean scores between the sexes in either questionnaire.

The questionnaires were filled in in the classroom, where they could see each other’s choices. The researchers think that may be the cause for the low scores.

Abdel-Hafez et al., The impact of acne vulgaris on the quality of life and psychologic status in patients from upper Egypt, 200932

Egypt

Patients with mild to severe acne, 14 years of age and older.

N=150 + 50 controls

To study the overall impact of acne vulgaris on the quality of life and psychologic functioning of patients in Egypt.

Source of scores:- Dermatology Life Quality Index (DLQI) (Total score range 0-30, 30 being 100% impairment)- Culture Free Self-Esteem Inventory – Adult Version (CFSEI-AD) (Total score range 0-32, 32 being 0% impairment)- Symptom Check List-90 (SCL-90-R)

Scores of relevance cover:- DLQI scores for males and females with acne.- CFSEI-AD scores for patients (total, female and male) and controls .- SCL-90-R scores for patients (total, female and male) and controls.

Significant DLQI scores Mean (SD): Male; Female.

Leisure: 2,8 (1,9); 1,9 (2,1) Total: 15,0 (7,5); 11,9 (7,7)

Significant CFSEI-AD scores Mean (SD): Patients; controls | male patients; female patients.

General: 7,8 (3,4); 10,2 (2,4) | 6,9 (3,5); 8,3 (3,3).Personal: 2,8 (2,1); 4,2 (2,2) | Total: 15,6 (6,3); 20,3 (4,9) | 14,3 (6,9); 16,2 (5,8)

SCL-90-R scores are in table 3 and 4 of the publication.

Significant correlations between duration of illness and severity and DLQI, SCL-90-R and CFSEI-AD scores. The longer the duration and the more severe the acne the worse the QOL.

Al Robaee, Assessment of general health and quality of life in patients with acne using a validated generic questionnaire, 200933

Saudi Arabia

Patients aged 14 to 45 years, with mild to very severe acne vulgaris.

N=454

To assess acne patients’ view of their general health and quality of life.

Source of scores:- SF-36 questionnaire (0-100, the higher the score, the better the health state)

Scores of relevance cover:- SF-36 scores for patients with acne.- Separate SF-36 scores on disease grade, disease duration, sex, residence, education for patients with acne.

Total mean (SD) SF-36 scores: Physical functioning; role physical; bodily pain; general health; vitality; social functioning; role emotional; mental health: 55,43 (28,14); 52,31 (37,17); 72,65 (20,29); 66,35 (15,04); 59,81 (15,98); 74,75 (20,64); 52,72 (40,49); 60,47 (17,91).

Scores on all the separate parameters are in table 2 and 3 of the publication.

Ismail et al., Quality of life in patients with acne in Erbil city, 201234

Iraq

Patients aged 11 to 36 years, with mild to severe acne vulgaris.

N=510

To determine the impact of acne and its clinical severity on health related quality of life.

Source of scores:- Cardiff Acne Disability Index (CADI)

Scores of relevance cover:There are no scores stated in this publication. The subjects were divided in two groups: low CADI scores <8 and high CADI scores >8. The results are shown as what percentage of the subjects are in the low and high score group per parameter.

Association between age and quality of life impairment (P<0.001): Patients aged 21-25 have higher scores.

QOL was more impaired (47,2%)* among female than among males (37,6%)* (P = 0,038).

Significant association between grading of acne and QOL impairment (P<0,0001).

QOL was more impaired among urban (46,8%)* than among rural (34,2%)* patients (P = 0,016).

* Percentage of the subjects in the ‘high CADI score’-group.

Janković et al., Quality of life among schoolchildren with acne: Results of a cross-sectional study, 201235

Serbia

Patients aged 15 to 18 years, with self-reported acne.

N=353

To assess health-related quality of life (HRQoL) among Serbian adolescents with acne.

Source of scores:- Children’s Dermatology Life Quality Index (CDLQI) (Total score range 0-30, 30 being 100% impairment)- Cardiff Acne Disability Index (CADI) (Score range 0-15, 15 being 100% impairment)

Scores of relevance cover:- Scores for adolescents with self-reported acne.- Scores for male and female adolescents with self-reported acne.- Scores for self-reported acne in adolescents with a coexisting disease or not.

Mean (SD) CDLQI; Mean (SD) CADI:

- Scores for adolescents with self-reported acne: 4,35; 3,57.- Scores for female adolescents with self-reported acne: 5,06 (5,88)*; 4,03 (2,89)- Scores for male adolescents with self-reported acne: 4,25 (4,74)*; 3,32 (2,54)- Scores for self-reported acne in adolescents with a coexisting disease: 6,03 (6,45); 4,14 (3,13)*- Scores for self-reported acne in adolescents without coexisting disease: 4,30 (4,89); 3,50 (2,59)*

There was good correlation between the 2questionnaires (Rho = 0.66).

*Not significantSafizadeh et al., Quality of Life in Iranian Patients with Acne, 201236

Iran

Patients aged 13 to 33 years, with mild to severe acne vulgaris.

N=220

To investigate the health-relatedquality of life in patients with acne in an Iranian context.

Source of scores:- Dermatology Life Quality Index (DLQI)- Cardiff Acne Disability Index (CADI)- Grading of the acne by the Global Acne Grading scale (GAG).

Scores of relevance cover:- Scores for patients with acne vulgaris.

Mean (SD) DLQI; Mean (SD) CADI:6,42 (4,77); 5,97 (2,97).

Quality of life is affected by severity of acne (P<0,01).

Subjects with university degrees had better quality of life in comparison to other subjects (P < 0,01).

Tasoula et al., The impact of acne vulgaris on quality of life and psychic health in young adolescents in Greece: Results of a population survey, 20126

Greece

Patients aged 11-19 years, with self-reported mild to severe acne.

N=784

To investigate the impact of acne vulgaris and its severity on Quality of Life of young adolescents in Greece.

Source of scores:- Children’s Dermatology Life Quality Index (CDLQI)

Scores of relevance cover:- CDLQI scores for patients with acne- CDLQI scores for mild, moderate and severe acne- CDLQI scores for boys and girls with acne

The impact on quality of life is associated with theseverity of the acne.Stress and heredity are correlated with acne and its severity.Girls and boys are equally affected.

Mean CDLQI scores: Total; mild; moderate; severe: 4,02; 2,94; 5,4; 12,05.

Table 9: An overview of pharmacoeconomic studies regarding the treatment of acne vulgaris

Study, year and country Interventions Method

Summary of model Key data sources Outcome measure Costs Key drivers

Warren et al., Clinical outcome and cost analysis of isotretinoin versus conventional regimens in the treatment of moderate acne vulgaris in male patients, 199837


- Isotretinoin (0,75-1 mg/kg/day) vs conventional therapy

Conventional therapy:- Combination: oral antibiotic + one or more topical preparations- Single drug: oral antibiotic or topical medication

CEA - Patients: Male 15-30 years of age, moderate acne (N=107)- Time window: Time required for complete clearing of inflammatory lesions (0 months to 4 years) and costs per month.

Efficacy: Results from this same study.

Costs: actual physician andlaboratory billings and the retail price of medication.

Costs, complete clearance of inflammatory lesions

Isotretinoin; conventional therapy

Mean monthly costs: $329; $112 (Medication, laboratory, physician: $216, $60, $53; $86, $0, $26).

Mean costs per treatment course:- Without regard to outcome: $1.855; $1.419- With complete clearing:$2.252; $16.004- Factored by mean number of months to clear: $1.770; $1.711

Current exchange rate: 1 Dollar = 0,76 Euro

- Cost of treatment

Wessels et al., The cost-effectiveness of isotretinoin in the treatment of acne part 1-3, 199938

South Africa

- Isotretinoin (1mg/kd/day) (i)- Oral antibiotics taken as chronic medication (ii)- Oral antibiotic + anti-androgen (iii)- Isotretinoin after two failed courses of antibiotics (SA guideline) (iv)

CMA (CEA)

- Markov model- Patients: Acne- Time window: 120 months- Perspective: Funder of health care- Discount rate costs: 0%- Sensitivity analyses: isotretinoin relapse rate, oral antibiotic costs, costs of oral antibiotic regimens include the costs of topical therapy.

Efficacy: Results from the meta-analysis in this same study.

Costs: Costs from the profiling study in this same study, retail drug prices from the ‘Blue Book’ April 1998 and for physicianconsultations and pathology rates the RepresentativeAssociation for Medical Schemes was used.

Costs, the eradication of acne (for the systemic isotretinoin therapy); andthe clinical control of the disease (for the oral antibiotic based therapies)

Break-even points with regimen 1 (i): ii; iii; iv: 50 months; 35 months; 10 months.

Costs i; ii; iii; iv:After 2 years: R8.941; R4.541; R6.228; R9.702After 5 years: R8.941; R10.428; R14.327; R9.983After 10 years: R8.941; R18.887; R25.966; R10.387

CEA: Cost/Successful treatment i;ii;iii;iv:R8.941; n/a; n/a; R.10.529

Current exchange rate: 1 Rand = 0,077 Euro

- Cost of treatment- Relapse rates

Bossuyt et al., Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline, 200339

United Kingdom and Belgium

Lymecycline vs minocycline(12 weeks)

CMA - Patients: Acne patients (N=134), between 12-30 years of age, moderate acne- Perspective: UK National Health Service- Time window: 12 weeks- Discount rate costs: 0%- Only direct costs of treatment (the medicine costs)


Costs: NHS, Monthly Index of Medical Specialities (April 2002 issue)

Costs, global assessment of improvement(lesion count, adverse events)

Lymecycline; minocycline

Total cost per treatment:£17,88; £70,46.

Total cost per treatment for a patient cured: £18,17; £77,00.

Current exchange rate: 1 Pound = 1,16 Euro

- Efficacy- Safety- Cost-effectiveness

Ozolins et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne, 200530

United Kingdom

- 500 mg oral oxytetracycline twice daily (b.d.) + topical vehicle control b.d.- 100 mg oral Minocin MR® (minocycline) once daily (o.d.) + topical vehicle control b.d.- Topical Benzamycin® (3% erythromycin + 5% benzoyl peroxide) b.d. + oral placebo o.d.- Topical Stiemycin® (2% erythromycin) o.d. + topical Panoxyl® Aquagel (5% benzoyl peroxide) o.d. + oral placebo o.d.- Topical Panoxyl® Aquagel (5% benzoyl peroxide) b.d. + oral placebo o.d.

CEA - Patients: Patients with mild to moderate inflammatory acne (N=649)- Time window: 18 weeks


Costs: Drug costs: British National Formulary (September 2001), referral to GP and dermatology specialist: University of Kent figures (2000).

- Costs of treatment (drug costs, cost of referral back to GP, referral to dermatology specialist)- Ratio of patient global at week 12,18 to cost of weeks on treatment- Ratio of lesion count change at week 12,18 to cost of weeks on treatment- Ratio of WTP (week 18) to cost of weeks on treatment- Ratio of WTP (week 18) to cost of weeks on treatment- WTP at week 18 by patient global categories- WTP at week 0 by baseline Burke and Cunliffe grade

Benzoyl peroxide was most cost-effective and minocycline was least cost-effective(difference in means –0.051 units/£, 95% CI –0.063 to –0.039).

More results are in tables 35 to 39 and 121 to 126 of the publication.

- Efficacy- Cost-effectiveness

Vreemde valuta omrekenen naar euro’s? Alleen als er dan iets vergeleken kan worden

[1] Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol 2013;168(3):474-485.

[2] Degitz K, Placzek M, Borelli C, Plewig G. Pathophysiology of acne. JDDG: Journal der Deutschen Dermatologischen Gesellschaft 2007;5(4):316-323.

[3] Collier CN, Harper JC, Cantrell WC, Wang W, Foster KW, Elewski BE. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008 1;58(1):56-59.

[4] Mittmann N, Trakas K, Risebrough N, Liu BA. Utility Scores for Chronic Conditions in a Community-Dwelling Population. Pharmacoeconomics 1999 04;15(4):369-376.

[5] Klassen AF, Newton JN, Mallon E. Measuring quality of life in people referred for specialist care of acne: Comparing generic and disease-specific measures. J Am Acad Dermatol 2000 8;43(2, Part 1):229-233.

[6] Tasoula E, Gregoriou S, Chalikias J, Lazarou D, Danopoulou I, Katsambas A, et al. The impact of acne vulgaris on quality of life and psychic health in young adolescents in Greece: results of a population survey. An Bras Dermatol 2012;87:862-869.

[7] College voor Zorgverzekeringen. Farmacotherapeutisch Kompas. Available at: http://www.fk.cvz.nl/. Accessed 7/29, 2013.

[8] Nederlands Huisartsen Genootschap. NHG-Standaard Acne. Available at: https://www.nhg.org/standaarden/volledig/nhg-standaard-acne. Accessed 7/29, 2013.

[9] Nederlandse Vereniging voor Dermatologie en Venereologie. Samenvatting Richtlijnen Dermatologie 2012: Acne. 2012; Available at: http://www.huidarts.info/documents/uploaded_file.aspx?id=602. Accessed 7/29, 2013.

[10] National Institute for Health and Care Excellence. Clinical Knowledge Summaries: Acne vulgaris. Available at: http://cks.nice.org.uk/acne-vulgaris. Accessed 7/29, 2013.

[11] Groninger Apotheken Vereniging. Groninger Formularium. 9th ed.; 2011.

[12] College voor Zorgverzekeringen. Medicijnkosten. Available at: http://www.medicijnkosten.nl/. Accessed 7/29, 2013.

[13] Langner A, Sheehan-Dare R, Layton A. A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide (Duac®) and erythromycin + zinc acetate (Zineryt®) in the treatment of mild to moderate facial acne vulgaris. Journal of the European Academy of Dermatology and Venereology 2007;21(3):311-319.

[14] Tunca M, Akar A, Ozmen I, Erbil H. Topical nadifloxacin 1% cream vs. topical erythromycin 4% gel in the treatment of mild to moderate acne. Int J Dermatol 2010;49(12):1440-1444.

[15] Electronic Medicines Consortium UK. eMC: Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/. Accessed 7/30, 2013.

http://www.medicines.org.uk/emc/

http://www.medicijnkosten.nl/

http://cks.nice.org.uk/acne-vulgaris

http://www.huidarts.info/documents/uploaded_file.aspx?id=602

https://www.nhg.org/standaarden/volledig/nhg-standaard-acne

http://www.fk.cvz.nl/

[16] Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther 2002 7;24(7):1117-1133.

[17] Ko H, Song M, Seo S, Oh C, Kwon K, Kim M. Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerability. Journal of the European Academy of Dermatology and Venereology 2009;23(3):245-250.

[18] Green LJ, Del Rosso JQ. Efficacy and Tolerability of a Three-Step Acne System Containing a Solubilized Benzoyl Peroxide Lotion versus a Benzoyl Peroxide/Clindamycin Combination Product. J Clin Aesthet Dermatol 2008;1(3):16-20.

[19] Seidler EM, Kimball AB. Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne. J Am Acad Dermatol 2010 7;63(1):52-62.

[20] Thiboutot DM, Weiss J, Bucko A, Eichenfield L, Jones T, Clark S, et al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: Results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 2007 11;57(5):791-799.

[21] Gollnick HPM, Draelos Z, Glenn MJ, Rosoph LA, Kaszuba A, Cornelison R, et al. Adapalene/benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 2009;161(5):1180-1189.

[22] Tan J, Gollnick HP, Loesche C, Ma YM, Gold LS. Synergistic efficacy of adapalene 0.1%-benzoyl peroxide 2.5% in the treatment of 3855 acne vulgaris patients. J Dermatol Treat 2011 08/01; 2013/07;22(4):197-205.

[23] Feucht CL, Allen BS, Chalker DK, J. Jr. GS. Topical erythromycin with zinc in acne: A double-blind controlled study. J Am Acad Dermatol 1980 11;3(5):483-491.

[24] Schachner L, Eaglstein W, Kittles C, Mertza P. Topical erythromycin and zinc therapy for acne. J Am Acad Dermatol 1990 2;22(2, Part 1):253-260.

[25] CHU A, HUBER FJ, PLOTT RT. The comparative efficacy of benzoyl peroxide 5%/erythromycin 3% gel and erythromycin 4%/zinc 1.2% solution in the treatment of acne vulgaris. Br J Dermatol 1997;136(2):235-238.

[26] College voor Zorgverzekeringen. Farmacotherapeutisch Kompas: Middelen bij huidaandoeningen. Available at: http://www.fk.cvz.nl/Inleidendeteksten/I/inl%20middelen%20bij%20huidaandoeningen.asp. Accessed 7/29, 2013.

[27] Chen SC, Bayoumi AM, Soon SL, Aftergut K, Cruz P, Sexton SA, et al. A Catalog of Dermatology Utilities: A Measure of the Burden of Skin Diseases. Journal of Investigative Dermatology Symposium Proceedings 2004 03;9(2):160-168.

[28] Chen CL, Kuppermann M, Caughey AB, Zane LT. A community-based study of acne-related health preferences in adolescents. Arch Dermatol 2008 08/01;144(8):988-994.

[29] Mosam A, Vawda NB, Gordhan AH, Nkwanyana N, Aboobaker J. Quality of life issues for South Africans with acne vulgaris. Clin Exp Dermatol 2005;30(1):6-9.

http://www.fk.cvz.nl/Inleidendeteksten/I/inl%20middelen%20bij%20huidaandoeningen.asp

http://www.fk.cvz.nl/Inleidendeteksten/I/inl%20middelen%20bij%20huidaandoeningen.asp

[30] Ozolins M, Eady E, Avery A, Cunliffe W, O'Neill C. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 2005 01/12;9(1):212.

[31] Walker N, Lewis-Jones M. Quality of life and acne in Scottish adolescent schoolchildren: use of the Children's Dermatology Life Quality Index© (CDLQI) and the Cardiff Acne Disability Index© (CADI). Journal of the European Academy of Dermatology and Venereology 2006;20(1):45-50.

[32] Abdel-Hafez K, Mahran AM, Hofny ERM, Mohammed KA, Darweesh AM, Aal AA. The impact of acne vulgaris on the quality of life and psychologic status in patients from upper Egypt. Int J Dermatol 2009;48(3):280-285.

[33] Al Robaee A. Assessment of general health and quality of life in patients with acne using a validated generic questionnaire. Acta Dermatovenerol Alp Panonica Adriat 2009;18(4):157-164.

[34] Ismail K, Mohammed-Ali K. Quality of life in patients with acne in Erbil city. Health and Quality of Life Outcomes 2012 06/06;10(1):1-4.

[35] Jankovic S, Vukicevic J, Djordjevic S, Jankovic J, Marinkovic J. Quality of life among schoolchildren with acne: Results of a cross-sectional study. Indian Journal of Dermatology, Venereology & Leprology 2012 Jul;78(4):454-458.

[36] Safizadeh H, Shamsi-Meymandy S, Naeimi A. Quality of life in Iranian patients with acne. Dermatol Res Pract 2012 2012 February 15.

[37] Warren KJ, Cruz PD. Clinical outcome and cost analysis of isotretinoin versus conventional regimens in the treatment of moderate acne vulgaris in male patients. Pediatr Dermatol 1998;15(4):329-331.

[38] Wessels F, Anderson AN, Kropman K. The cost-effectiveness of isotretinoin in the treatment of acne, Part 1-3. S Afr Med J 1999;89(7):780-794.

[39] Bossuyt L, Bosschaert J, Richert B, Cromphaut P, Mitchell T, Al Abadie M, et al. Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline. Eur J Dermatol 2003;13(2):130-135.

Documents

Acne Vulgaris