Skin disorders. Seborrhoeic dermatitis Search date April 2010 Luigi Naldi ...

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1 Seborrhoeic Search date April 21 Luigi Naldi ABSTRACT INTRODUCTION: Seborrhoeic affects at least 1% of the population. Malassezia (Pityrosporum) ovale is thought to be the causative organism, and causes inflammation by still poorly defined mechanisms. Seborrhoeic tends to relapse after treatment. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of topical treatments for seborrhoeic of the scalp in adults? What are the effects of topical treatments for seborrhoeic of the face and body in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 21 (Clinical Evidence reviews are updated periodically, please check our website for the most uptodate version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, s, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: bifonazole, emollients, ketoconazole, lithium succinate, selenium sulphide, tar shampoo, terbinafine, and topical corticosteroids (betamethasone valerate, clobetasol propionate, clobetasone butyrate, hydrocortisone, mometasone furoate). QUESTIONS What are the effects of topical treatments for seborrhoeic of the scalp in adults? What are the effects of topical treatments for seborrhoeic of the face and body in adults? TOPICAL TREATMENTS FOR SEBORRHOEIC DER MATITIS OF SCALP Beneficial Ketoconazole Likely to be beneficial Bifonazole Selenium sulphide Tar shampoo Corticosteroids (topical) (hydrocortisone, betamethasone valerate, clobetasone butyrate, mometasone furoate, clobetasol propionate)* INTERVENTIONS Corticosteroids (topical) (hydrocortisone, betamethasone valerate, clobetasone butyrate, mometasone furoate, clobetasol propionate; short term episodic treatment in adults)* Unknown effectiveness Emollients Lithium succinate Selenium sulphide Terbinafine Topical calcineurin inhibitors (pimecrolimus, tacrolimus) Unknown effectiveness Terbinafine TOPICAL TREATMENTS FOR SEBORRHOEIC DER MATITIS OF FACE OR BODY Beneficial Ketoconazole Likely to be beneficial Bifonazole To be covered in future updates Combination agents (steroid/antifungal) Oral antifungal agents Zinc shampoo Salicylic acid shampoo Tea tree oil for dandruff Immune system creams Footnote *Based on consensus. Key points Seborrhoeic affects at least 1% of the population and causes red patches with greasy scales on the face, chest, skin flexures, and scalp. The cause of seborrhoeic is unknown. Malassezia yeasts are thought to have an important role. The inflammatory process may be mediated in susceptible people by fungal metabolites, namely free fatty acids, released from sebaceous triglycerides. The lipid layer of Malassezia can also modulate proinflammatory cytokine production by keratinocytes. Known risk factors include immunodeficiency, neurological or cardiac disease, and alcoholic pancreatitis. In this review, however, we deal with treatment in immunocompetent adults who have no known predisposing conditions. BMJ Publishing Group Ltd 21. All rights reserved Clinical Evidence 21;12:1713

2 Seborrhoeic tends to relapse after treatment. In adults with seborrhoeic of the scalp, antifungal preparations containing ketoconazole improve symptoms compared with placebo. Bifonazole and selenium sulphide are also likely to be effective, but we don't know whether terbinafine is beneficial as we found no s. We found insufficient evidence to fully assess the effectiveness of short courses of topical corticosteroids; however, there is consensus that topical corticosteroids are effective in treating seborrhoeic of the scalp in adults. We found limited evidence that clobetasol propionate.5% may improve some symptoms of seborrhoeic. Tar shampoo may reduce scalp dandruff and redness compared with placebo. Seborrhoeic In adults with seborrhoeic of the face and body, antifungal preparations containing ketoconazole cream or gel and bifonazole cream may improve skin symptoms compared with placebo. There is consensus that short courses of topical corticosteroids are effective, although we found no s that assessed this. We don't know whether terbinafine or selenium sulphide are also beneficial as we found no s. We don't know whether pimecrolimus, a topical calcineurin inhibitor, is beneficial, as we found few s. We don't know whether emollients or topical lithium succinate improve lesions compared with no treatment. DEFINITION Seborrhoeic occurs in areas of the skin with a rich supply of sebaceous glands and manifests as red, sharply marginated lesions with greasy looking scales. On the face it mainly affects the medial aspect of the eyebrows, the area between the eyebrows, and the nasolabial folds. It may also affect the skin on the chest (commonly presternal) and the flexures. On the scalp it manifests as dry, flaking desquamation (dandruff) or yellow, greasy scaling with erythema. Dandruff is a lay term commonly used in the context of mild seborrhoeic of the scalp. However, any scalp condition that produces scales could be labelled as dandruff. There is also an infantile variant, commonly affecting the scalp, flexures, and genital area, but this infantile variant seems to have a different pathogenesis from adult seborrhoeic. Common differential diagnoses for seborrhoeic of the scalp are psoriasis, eczema (see review on atopic eczema), and tinea capitis (see table 1, p 26 ). INCIDENCE/ PREVALENCE Seborrhoeic is estimated to affect about 1% of the general population. [1] AETIOLOGY/ The cause of seborrhoeic is unknown and the disease seems to be multifactorial. RISK FACTORS Malassezia yeasts, a genus classified in 7 species, are considered to have an important role in seborrhoeic, producing an inflammatory reaction that seems to be mediated by free fatty acids, released from sebaceous triglycerides by fungal enzymes such as lipases. The lipid layer of Malassezia can also modulate proinflammatory cytokine production by keratinocytes. Conditions that have been reported to predispose to seborrhoeic include HIV, [2] neurological conditions such as Parkinson's disease, neuronal damage such as facial nerve palsy, [3] spinal injury, [4] ischaemic heart disease, [5] and alcoholic pancreatitis. [6] In this review, we deal with treatment in immunocompetent adults who have no known predisposing conditions. PROGNOSIS Seborrhoeic is a chronic condition that tends to flare and remit spontaneously, and is [1] [7] prone to recurrence after treatment. AIMS OF To reduce the symptoms and signs of seborrhoeic with minimal adverse effects. Most INTERVENTION therapeutic options aim to reduce colonisation with Malassezia species and reduce inflammation, although they tend to palliate rather than cure. OUTCOMES METHODS, including itching, scale, and erythema; adverse effects of treatment. Clinical Evidence search and appraisal April 21. The following databases were used to identify studies for this systematic review: Medline 1966 to April 21, Embase 198 to April 21, and The Cochrane Database of Systematic Reviews 21, April 21 (online) (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 21, Issue 2. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of s (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of s and s in any language, BMJ Publishing Group Ltd 21. All rights reserved

3 Seborrhoeic at least single blinded, and containing more than 2 individuals. Trials of less than 4 weeks' duration had to have at least 9% followup; s lasting 4 weeks or longer had to have at least 8% followup. Trials of less than 1 week were excluded. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of s and s where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 27 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website ( QUESTION What are the effects of topical treatments for seborrhoeic of the scalp in adults? OPTION KETOCONAZOLE SCALP PREPARATIONS For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. In adults with seborrhoeic of the scalp, antifungal preparations containing ketoconazole improve symptoms compared with placebo. Benefits and harms Ketoconazole shampoo versus placebo: [8] We found no systematic review. We found 6 s. [9] [1] [11] [12] Ketoconazole shampoo compared with placebo Ketoconazole shampoo is more effective than placebo at improving scalp symptoms such as scaling, itching, redness, and dandruff at 4 weeks in people with seborrhoeic of the scalp (moderatequality evidence). Scalp scaling [8] Crossover design 2 people (16 male, 4 female) with either dandruff or seborrhoeic (no distinction made between these; proportion with seborrhoeic not reported) Approximate median change in participantrated scaling score, 4 weeks 2 with ketoconazole (2% shampoo) +15 with placebo (shampoo base Scalp itching and scaling measured on a 1mm visual analogue scale (VAS; = none to 1 = "worst ever") Median scores precrossover approximated from graphs [9] 53 people with moderate to severe dandruff, 28 (53%) of whom had seborrhoeic Mean change in adherent dandruff score, 15 days 12 with ketoconazole (2% shampoo) 7 with placebo (shampoo base P <.5 Ketoconazole BMJ Publishing Group Ltd 21. All rights reserved.... 3

4 [9] 53 people with moderate to severe dandruff, 28 (53%) of whom had seborrhoeic Six scalp areas assessed; = no scaling to 1 = extremely severe scaling Mean change in adherent dandruff score, 29 days 19 with ketoconazole (2% shampoo) 13 with placebo (shampoo base P <.5 Seborrhoeic Ketoconazole Six scalp areas assessed; = no scaling to 1 = extremely severe scaling [1] 3armed 246 people with moderate to severe dandruff arm assessed the effects of selenium sulphide 2.5% shampoo % reduction in mean adherent dandruff score from baseline, 29 days 73.% with ketoconazole (2% shampoo) 44.5% with placebo (shampoo base Absolute numbers not reported 146 people in this (97 in the ketoconazole 2% group, 49 in the placebo group) Six scalp areas assessed; = none and 9 to 1 = severe/heavy [11] 3armed 163 people with seborrhoeic or dandruff arm assessed the effects of coal tar 4% plus ciclopirox olamine 1% shampoo Mean change in clinicianrated scaling score ( = none to 4 = very severe), 29 days 1.2 with ketoconazole (2% shampoo).3 with placebo (shampoo base 18 people in this (54 in each arm) P <.1 Ketoconazole [12] 3armed 35 people with Mean % change in participantassessed scaling, 4 weeks 5.5% with ketoconazole shampoo 2% arm assessed ciclopirox olamine 32.6% with placebo 1.5% shampoo. Absolute numbers not reported included people aged <16 years; see further information on Scaling measured on a 1mm VAS ( = none to 1 = "worst ever") studies for details 2 people in this (15 receiving ketoconazole, 5 receiving placebo) [12] 3armed 35 people with arm assessed ciclopirox olamine 1.5% shampoo. Technicianassessed change in scaling (rated as cured or improved), 4 weeks 113/146 (77%) with ketoconazole shampoo 2% 35/49 (71%) with placebo included peo 2 people in this (15 receiving ketoconazole, 5 receiving placebo) ple aged <16 years; see further information on studies for details Cure defined as a value > at baseline and a value of at day BMJ Publishing Group Ltd 21. All rights reserved.... 4

5 5armed 29; improved defined as a lower value at day 29 (but not ) than at baseline (Mantel Haenszel test for linear association) Loose scaling, 4 weeks with ketoconazole foaming gel 2% 3 with vehicle shampoo (placebo) clobetasol propi Absolute results reported graphically onate shampoo.5% used for different durations 22 people in this See further information on studies for details on differences between active treatment and placebo preparation Seborrhoeic Reported as not significant Not significant Scalp itching [8] Crossover design 2 people (16 male, 4 female) with either dandruff or seborrhoeic (no distinction made between these; proportion with seborrhoeic not reported) Approximate median change in participantrated itching score, 4 weeks 2 with ketoconazole (2% shampoo) +8 with placebo (shampoo base Itching measured on a 1mm VAS ( = none to 1 = "worst ever") Median scores precrossover approximated from graphs [12] 35 people with scalp arm assessed ciclopirox olamine 1.5% shampoo. included people aged <16 years; see further information on studies for more details Mean % change in participantassessed itching, 4 weeks 48.8% with ketoconazole shampoo 2% 34.1% with placebo Itching measured on a 1mm VAS ( = none to 1 = "worst ever") 2 people in this (15 receiving ketoconazole, 5 receiving placebo) 5armed Scalp itching, 4 weeks with ketoconazole foaming gel 2% 3 with vehicle shampoo (placebo) clobetasol propi Absolute results reported graphically onate shampoo.5% used for different durations 22 people in this See further information on studies for details on differences between active treatment and placebo preparation Reported as not significant Not significant Scalp redness (erythema) [11] 3armed 163 people with seborrhoeic or dandruff arm assessed coal tar Mean change in clinicianrated redness score ( = none to 4 = very severe), 29 days 1.3 with ketoconazole (2% shampoo) P <.1 Ketoconazole BMJ Publishing Group Ltd 21. All rights reserved.... 5

6 [12] 4% plus ciclopirox olamine 1% shampoo 35 people with scalp arm assessed ciclopirox olamine 1.5% shampoo. included people aged <16 years; see further information on studies for details.5 with placebo (shampoo base 18 people in this (54 in each arm) Technician's overall assessment of clinical changes in erythema (rated as cured, much improved, or improved), 4 weeks 9/146 (62%) with ketoconazole 22/49 (45%) with placebo 2 people in this assessment (15 receiving ketoconazole, 5 receiving placebo) Seborrhoeic Cure defined as a value > at baseline and a value of at day 29; improved defined as a lower value at day 29 (but not ) than at baseline (Mantel Haenszel test for linear association) 5armed 3 clobetasol propionate shampoo.5% used for different durations Erythema, on a scale from to 3, 4 weeks.1 with ketoconazole foaming gel 2%.7 with vehicle shampoo (placebo) 22 people in this See further information on studies for details on differences between active treatment and placebo preparation P =.27 ketoconazole Global severity [9] 53 people with moderate to severe dandruff, 28 (53%) of whom had seborrhoeic Proportion of people responding to treatment (global evaluation of completely cleared, excellent, or good), 29 days 22/28 (79%) with ketoconazole (2% shampoo) P =.4 Ketoconazole 9/24 (38%) with placebo (shampoo base [1] 3armed 246 people with moderate to severe dandruff arm assessed the effects of selenium sulphide 2.5% shampoo Proportion of people responding to treatment (global evaluation of completely cleared, excellent, or good), 29 days 65% with ketoconazole (2% shampoo) 29% with placebo (shampoo base P <.1 Ketoconazole Absolute numbers not reported 146 people in this (97 with ketoconazole, 49 with placebo) [11] 3armed 163 people with seborrhoeic or dandruff arm assessed the effects of coal tar 4% plus ciclopirox Area of scalp affected by seborrhoeic, 29 days with ketoconazole (2% shampoo) with placebo (shampoo base Reported as not significant P value not reported Not significant BMJ Publishing Group Ltd 21. All rights reserved.... 6

7 [12] 3armed olamine 1% shampoo 35 people with arm assessed ciclopirox olamine 1.5% shampoo. included people aged <16 years; see further information on studies for details. 18 people in this (54 in each arm) Mean change from baseline in area of (cm 2 ), 4 weeks 41.4 cm 2 with ketoconazole 2% shampoo 2. cm 2 with placebo Absolute numbers not reported 2 people in this (15 receiving ketoconazole, 5 receiving placebo) Seborrhoeic 5armed 3 clobetasol propionate shampoo.5% used for different durations Total symptom severity, on a scale from to 3, 4 weeks.7 with ketoconazole foaming gel 2% 2.6 with vehicle shampoo (placebo) Absolute results reported graphically P less than or equal to.2 ketoconazole 22 people in this See further information on studies for details on differences between active treatment and placebo preparation [8] Crossover design 2 people (16 male, 4 female) with either dandruff or seborrhoeic (no distinction made between these; proportion with seborrhoeic not reported), 4 weeks with ketoconazole (2% shampoo) with placebo (shampoo base The reported that there were no adverse effects of treatment [9] [1] 3armed 53 people with moderate to severe dandruff, 28 (53%), 29 days with ketoconazole (2% shampoo) of whom had seborrhoeic with placebo (shampoo base without ketoconazole) 246 people with moderate to severe dandruff arm assessed the effects of selenium sulphide 2.5% shampoo The reported that there were no adverse effects of treatment, 29 days with ketoconazole (2% shampoo) with placebo (shampoo base Absolute numbers not reported BMJ Publishing Group Ltd 21. All rights reserved.... 7

8 5armed 3 clobetasol propionate shampoo.5% used for different durations The reported that there were no adverse effects of treatment 146 people in this (97 in ketoconazole arm, 49 in placebo arm), 4 weeks with ketoconazole foaming gel 2% with vehicle shampoo (placebo) The reported that there were no serious adverse events See further information on studies for details on differences between active treatment and placebo preparation Seborrhoeic Scalp tenderness [11] 3armed 163 people with seborrhoeic or dandruff arm assessed the effects of coal tar 4.% plus ciclopirox olamine 1% shampoo Scalp tenderness, 29 days with ketoconazole (2% shampoo) with placebo (shampoo base The reported one instance of scalp tenderness that was probably related to ketoconazole treatment Eye stinging [12] 3armed 35 people with arm assessed ciclopirox olamine 1.5% shampoo (15 people). included people Eye stinging, 29 days 5/146 (3%) with ketoconazole 2% shampoo 2/49 (4%) with placebo Absolute numbers not reported Eye stinging was the most frequent adverse effect aged <16 years; 2 people in this (15 see further information on studies for ing placebo) receiving ketoconazole, 5 receiv more details [12] The included some children aged between 12 and 16 years old, which is outside our population of interest. However, as the mean age of participants was about 43 years, the proportion of children in the was unlikely to be high. This 5arm compared ketoconazole foaming gel 2%, clobetasol propionate shampoo.5% for 3 different durations, and a "clobetasol propionate vehicle" as the placebo treatment. The authors stated that: "Because of the different appearance of the shampoo and foaming gel preparations, blinding of the treatments' identity to the subjects was not possible. Blinding for investigators was maintained by using independent study personnel to dispense medication and collect returned medication." However, it is reasonable to assume that, in practice, participants were unaware of whether they were using an active treatment or the placebo. BMJ Publishing Group Ltd 21. All rights reserved.... 8

9 Seborrhoeic Comment: We found one large (1162 people aged at least 12 years, mean age about 45 years) [14] that assessed the effects of ketoconazole cream 2% (21 people), ketoconazole foam 2% (427 people), vehicle cream (15 people), and vehicle foam (42 people) on seborrhoeic of the scalp (62% of people in this ), face (33%), and body (5%). The did not carry out subgroup analyses for different body regions, and it included people aged <16 years. We cannot therefore draw conclusions regarding our specific questions and population of interest, but have chosen to mention this here as it is a large study that supports existing evidence that ketoconazole is beneficial in the treatment of seborrhoeic of the scalp and body. The found that ketoconazole foam significantly increased the proportion of people achieving treatment success (defined as Investigator's Static Global Assessment [ISGA] score of or 1 [on a scale of 4] at week 4; people with a baseline score of 2 must have improved to a score of ) compared with vehicle (placebo) foam (239/427 [56%] with ketoconazole foam v 176/42 [42%] with vehicle foam; P <.1), and that more people receiving ketoconazole cream achieved treatment success (56% with ketoconazole cream v 31% with vehicle cream; absolute numbers not reported; significance not assessed). OPTION BIFONAZOLE SCALP PREPARATIONS For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. In adults with seborrhoeic of the scalp, bifonazole is likely to be effective at treating symptoms. Benefits and harms Bifonazole shampoo versus placebo: We found no systematic review. We found one. [15] Bifonazole shampoo compared with placebo Bifonazole shampoo may be more effective at improving symptoms such as scaling and pruritus, and overall symptom severity at 6 weeks in people with seborrhoea or seborrhoeic of the scalp (lowquality evidence). Scalp scaling [15] 51 people with seborrhoea or seborrhoeic of the scalp Improvement in severity of scaling (graded by a clinician on a 4point scale from = none to 3 = severe), 6 weeks with bifonazole 1% shampoo P =.1 Bifonazole with placebo Pruritus [15] 51 people with seborrhoea or seborrhoeic of the scalp Improvement in severity of pruritus (graded by a clinician on a 4point scale from = none to 3 = severe), 6 weeks with bifonazole 1% shampoo P =.8 Bifonazole with placebo Global severity [15] 51 people with seborrhoea or seborrhoeic of the scalp Improvement in overall severity (graded by a clinician on a 4 point scale from = none to 3 = severe), 6 weeks P =.12 Bifonazole with bifonazole 1% shampoo BMJ Publishing Group Ltd 21. All rights reserved.... 9

10 with placebo Seborrhoeic [15] 51 people with seborrhoea or seborrhoeic of the scalp, 6 weeks with bifonazole 1% shampoo with placebo The reported "no major side effects" Comment: None. OPTION SELENIUM SULPHIDE SCALP PREPARATIONS For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. In adults with seborrhoeic of the scalp, selenium sulphide is likely to be effective at treating symptoms. Benefits and harms Selenium sulphide shampoo versus placebo: We found no systematic review. We found one. [1] Selenium sulphide shampoo compared with placebo Selenium sulphide shampoo may be more effective at reducing dandruff, and at increasing response to treatment at 29 days, in people with moderate to severe dandruff (lowquality evidence). Scalp scaling [1] 3armed 246 people with moderate to severe dandruff The third arm assessed the effects of ketoconazole 2% shampoo Randomisation was in a 2:2:1 ratio: selenium sul % Reduction in mean adherent dandruff score from baseline, 29 days 66.7% with selenium sulphide 2.5% shampoo 44.5% with placebo (shampoo base without selenium sulphide) Absolute numbers not reported Reported as significant P value not reported Selenium sulphide BMJ Publishing Group Ltd 21. All rights reserved.... 1

11 Global severity [1] 3armed phide 2.5% shampoo (1 people); ketoconazole 2% shampoo (97 people); and placebo (49 people) 246 people with moderate to severe dandruff The third arm assessed the effects of ketoconazole 2% shampoo Six scalp areas were assessed; dandruff score ranged from = none to 9 1 = severe/heavy 149 people in this Proportion of people responding to treatment (global evaluation of completely cleared, excellent, or good), 29 days 54.7% with selenium sulphide 2.5% shampoo 28.6% with placebo (shampoo base without selenium sulphide) Randomisation was in a 2:2:1 ra Absolute numbers not reported tio: selenium sulphide 2.5% sham 149 people in this poo (1 people); ketoconazole 2% shampoo (97 people); and placebo (49 people) P =.4 Seborrhoeic Selenium sulphide [1] 3armed 246 people with moderate to severe dandruff, 29 days with selenium sulphide 2.5% shampoo The third arm assessed the effects with placebo (shampoo base without selenium sulphide) of ketoconazole 2% shampoo Randomisation was in a 2:2:1 ratio: selenium sulphide 2.5% shampoo (1 people); ketoconazole 2% shampoo (97 people); and placebo (49 people) The reported infrequent adverse events with selenium sul phide shampoo, including pruritus or burning sensation of the scalp (3 people), eruption near the hair line (1 person), psoriasis (1 per son), lightening/bleaching of hair colour (2 people), orange staining of the scalp (1 person), and a chemical taste during shampooing (1 person) 149 people in this Comment: None. BMJ Publishing Group Ltd 21. All rights reserved

12 OPTION TAR SHAMPOO For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. In adults with seborrhoeic of the scalp, tar shampoo may reduce scalp dandruff and redness compared with placebo Benefits and harms Tar shampoo versus placebo: We found no systematic review. We found one. [11] Seborrhoeic Tar shampoo compared with placebo Tar shampoo is more effective than placebo at improving dandruff and redness at 29 days in people with seborrhoeic or dandruff (moderatequality evidence). Scalp scaling [11] 3armed 163 people with seborrhoeic or dandruff The third arm assessed the effects of ketoconazole (2% shampoo) Mean change in dandruff score from baseline (assessed by a technician), 29 days 31 with coal tar 4.% plus ciclopirox olamine 1% shampoo 19 with placebo (shampoo base P <.1 Tar shampoo 111 people in this See further information on studies for details of calculation of dandruff score [11] 3armed 163 people with seborrhoeic or dandruff The third arm assessed the effects of ketoconazole (2% shampoo) Scaling or area of seborrhoeic, 29 days with coal tar 4.% plus ciclopirox olamine 1% shampoo with placebo (shampoo base Reported as not significant Not significant 111 people in this Scalp redness (erythema) [11] 3armed 163 people with seborrhoeic or dandruff The third arm assessed the effects of ketoconazole (2% shampoo) Mean change in redness score from baseline, 29 days 1.2 with coal tar 4.% plus ciclopirox olamine 1% shampoo.6 with placebo (shampoo base Redness score graded by a clinician on a 5point scale from = none to 4 = very severe P <.5 Tar shampoo 111 people in this Global severity [11] 3armed 163 people with seborrhoeic or dandruff The third arm assessed the effects of ketoconazole (2% shampoo) Area of scalp affected by seborrhoeic, 29 days with coal tar 4.% plus ciclopirox olamine 1% shampoo with placebo (shampoo base Reported as not significant P value not reported Not significant 111 people in this BMJ Publishing Group Ltd 21. All rights reserved

13 [11] 3armed 163 people with seborrhoeic or dandruff, 29 days with coal tar 4.% plus ciclopirox olamine 1% shampoo The third arm assessed the effects with placebo (shampoo base of ketoconazole (2% shampoo) 111 people in this The reported no major adverse events Seborrhoeic [11] Dandruff score calculated by multiplying of affected area by severity; of affected area scored from = 1% to 4 = >7%; severity scored from 1 = small flakes resembling a white powder to 5 = flakes adhering to the scalp as white or yellow plates. Comment: OPTION None. TOPICAL CORTICOSTEROIDS (HYDROCORTISONE, BETAMETHASONE VALERATE, CLO BETASONE BUTYRATE, MOMETASONE FUROATE, CLOBETASOL PROPIONATE) For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. There is consensus that topical corticosteroids are effective in treating seborrhoeic of the scalp in adults. We found limited evidence that clobetasol propionate.5% may improve some symptoms of. We found no direct information from s about whether topical corticosteroids other than clobetasol propionate shampoo.5% are better than no active treatment for seborrhoeic of the scalp in adults. Benefits and harms Topical corticosteroids versus placebo: We found no systematic review. We found one. Clobetasol propionate shampoo.5% compared with placebo Clobetasol propionate shampoo.5% applied twice weekly for 2.5, 5, or 1 minutes may be more effective at 4 weeks in improving total symptom severity scores. Clobetasol propionate shampoo.5% applied twice weekly for 5 minutes may be more effective at improving erythema and itching. Clobetasol propionate shampoo.5% applied twice weekly for 1 minutes may be more effective at improving scaling. We don't know whether clobetasol propionate used for other durations is more effective at improving symptoms (very lowquality evidence). BMJ Publishing Group Ltd 21. All rights reserved

14 Total symptom severity 5armed clobetasol propionate.5% shampoo for 5 and 1 minutes, and ketoconazole 2% foaming gel Total symptom severity on a scale of to 3 ( = no symptoms, 3 = most severe), 4 weeks.8 with clobetasol propionate shampoo.5% used for 2.5 minutes 2.6 with vehicle shampoo (placebo) 22 people in this Seborrhoeic P less than or equal to.2 Clobetasol propionate.5% used for 2.5 minutes 5armed Total symptom severity, on a scale of to 3 ( = no symptoms, 3 = most severe), 4 weeks.6 with clobetasol propionate clobetasol propionate shampoo.5% used for 5 min.5% utes shampoo for with vehicle shampoo (placebo) and 1 minutes, and ketoconazole 2% foaming gel 22 people in this P less than or equal to.2 Clobetasol propionate.5% used for 5 minutes 5armed clobetasol propionate.5% shampoo for 2.5 and 5 minutes, and ketoconazole 2% foaming gel Total symptom severity, on a scale of to 3 ( = no symptoms, 3 = most severe), 4 weeks.7 with clobetasol propionate shampoo.5% used for 1 minutes 2.6 with vehicle shampoo (placebo) 22 people in this P less than or equal to.2 Clobetasol propionate.5% used for 1 minutes Scalp scaling 5armed Loose scaling, on a scale from to 3 ( = clear, 3 = worst), 4 weeks with clobetasol propionate shampoo.5% for 2.5 minutes clobetasol propi onate.5% shampoo for 5 and 1 minutes, and ketoconazole 2% foaming gel with vehicle shampoo (placebo) 22 people in this Reported as not significant Not significant 5armed clobetasol propionate.5% shampoo for 2.5 and 1 minutes, and ketoconazole 2% foaming gel Loose scaling, on a scale from to 3 ( = clear, 3 = worst), 4 weeks.4 with clobetasol propionate shampoo.5% for 5 minutes 1. with vehicle shampoo (placebo) 22 people in this P =.51 Not significant 5armed clobetasol propi Loose scaling, on a scale from to 3 ( = clear, 3 = worst), 4 weeks.3 with clobetasol propionate shampoo.5% for 1 minutes P =.27 Clobetasol propionate.5% for 1 minutes BMJ Publishing Group Ltd 21. All rights reserved

15 onate.5% shampoo for 2.5 and 5 minutes, and ketoconazole 2% foaming gel Scalp redness (erythema) 5armed clobetasol propionate.5% shampoo for 5 and 1 minutes, and ketoconazole 2% foaming gel 1. with vehicle shampoo (placebo) 22 people in this Erythema, on a scale of to 3 ( = clear, 3 = worst), 4 weeks with clobetasol propionate shampoo.5% for 2.5 minutes with vehicle shampoo (placebo) Absolute numbers not reported 22 people in this Seborrhoeic Reported as not significant Not significant 5armed clobetasol propionate.5% shampoo for 2.5 and 1 minutes, and ketoconazole 2% foaming gel Erythema, on a scale of to 3 ( = clear, 3 = worst), 4 weeks.1 with clobetasol propionate shampoo.5% for 5 minutes.7 with vehicle shampoo (placebo) 22 people in this P =.24 Clobetasol propionate.5% for 5 minutes Crossover design 5armed clobetasol propionate.5% shampoo for 2.5 and 5 minutes, and ketoconazole 2% foaming gel Erythema, on a scale of to 3 ( = clear, 3 = worst), 4 weeks with clobetasol propionate shampoo.5% for 1 minutes with vehicle shampoo (placebo) 22 people in this Reported as not significant Not significant Scalp itching 5armed Itching, measured on a 1mm analogue scale ( = no itching, 1 = worst), 4 weeks with clobetasol propionate shampoo.5% for 2.5 minutes clobetasol propi onate.5% shampoo for 5 and 1 minutes, and ketoconazole 2% foaming gel with vehicle shampoo (placebo) 22 people in this Reported as not significant Not significant 5armed clobetasol propionate.5% shampoo for 2.5 and 1 minutes, and ketoconazole 2% foaming gel Itching, measured on a 1mm analogue scale ( = no itching, 1 = worst), 4 weeks 4.8 mm with clobetasol propionate shampoo.5% for 5 minutes 34. mm with vehicle shampoo (placebo) 22 people in this P =.7 BMJ Publishing Group Ltd 21. All rights reserved

16 5armed Itching, measured on a 1mm analogue scale ( = no itching, 1 = worst), 4 weeks with clobetasol propionate shampoo.5% for 1 minutes clobetasol propi onate.5% shampoo for 2.5 and 5 minutes, and ketoconazole 2% foaming gel with vehicle shampoo (placebo) Seborrhoeic Reported as not significant Not significant Folliculitis 5armed seborrhoeic of the scalp clobetasol propionate.5% shampoo for 2.5 and 1 minutes, and ketoconazole 2% foaming gel Folliculitis, 4 weeks 1/11 with clobetasol propionate.5% shampoo for 5 minutes /11 with clobetasol propionate vehicle (placebo) 22 people in this Dry skin 5armed seborrhoeic of the scalp clobetasol propionate.5% shampoo for 2.5 and 5 minutes, and ketoconazole 2% foaming gel Dry skin, 4 weeks 1/11 with clobetasol propionate.5% shampoo for 1 minutes /11 with vehicle shampoo (placebo) Comment: Although limited evidence is available from a single small concerning clobetasol propionate shampoo.5%, there is consensus that topical corticosteroids are effective in treating seborrhoeic of the scalp in adults. OPTION TERBINAFINE SCALP PREPARATIONS For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether terbinafine is beneficial in adults with seborrhoeic of the scalp as no studies have been found. BMJ Publishing Group Ltd 21. All rights reserved

17 We found no direct information from s about whether terbinafine is better than no active treatment in adults with seborrhoeic of the scalp. Benefits and harms Terbinafine versus placebo: We found no systematic review or s (see comment below). Seborrhoeic Comment: QUESTION Terbinafine versus placebo: Terbinafine is not manufactured as a scalp preparation in the UK and is not known to be available worldwide. What are the effects of topical treatments for seborrhoeic of the face and body in adults? OPTION KETOCONAZOLE For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. Ketoconazole cream or gel may improve skin symptoms in adults with seborrhoeic of the face and body. Benefits and harms Ketoconazole versus placebo: We found no systematic review. We found two small s comparing ketoconazole 2% cream versus placebo, [16] [17] and one large comparing ketoconazole 2% gel versus placebo. [18] Ketoconazole compared with placebo Ketoconazole seems more effective at increasing the number of people successfully treated, and at improving symptoms such as erythema, scaling, papules, and pruritus, at 4 weeks (moderatequality evidence). [16] 2 people with seborrhoeic of the face (8% also had seborrhoeic of the scalp, 35% also had chest involvement, and 25% also had back involvement) Improvement in facial symptoms, 4 weeks 9/1 (9%) with ketoconazole (2% cream) /1 (%) with placebo Improvement measured as proportion of people whose facial symptoms improved by at least one symptom grade from baseline (severity of symptoms graded on a 4point scale from = none to 3 = severe) People in the ketoconazole group could also use topical ketoconazole 2% shampoo P value not reported BMJ Publishing Group Ltd 21. All rights reserved

18 [17] 37 people with seborrhoeic Change in approximate mean sum of symptom scores from baseline, 4 weeks 19 with ketoconazole (2% cream) 13 with placebo Seborrhoeic P value not reported Symptom score was a composite clinical score in which 8 sites were graded for erythema, scaling, papules, and pruritus; range not reported Approximate mean scores were extracted from graphs because data were not tabulated [18] 459 people with seborrhoeic Proportion of people classed as successfully treated, 4 weeks P =.14 58/229 (25%) with ketoconazole (2% gel) 32/23 (14%) with placebo (vehicle gel) Ketoconazole See further information on studies for definition of successful treatment [16] 2 people with seborrhoeic of the face (8% also had seborrhoeic of the scalp, 35% also had chest involvement, and 25% also had back involvement), 4 weeks with ketoconazole (2% cream) with placebo The reported no adverse effects of treatment People in the ketoconazole group could also use topical ketoconazole 2% shampoo [17] 37 people with seborrhoeic, 4 weeks with ketoconazole (2% cream) with placebo The reported that there were no adverse effects of treatment [18] 459 people with seborrhoeic Proportion of people with application site burning, 4 weeks 2.6% with ketoconazole (2% gel) 2.6% with placebo (vehicle gel) Absolute numbers not reported reported were treatmentrelated adverse effects occurring in 1% or more of people BMJ Publishing Group Ltd 21. All rights reserved

19 [18] 459 people with seborrhoeic Proportion of people with treatmentrelated erythema, 4 weeks 1.7% with ketoconazole (2% gel) 1.3% with placebo (vehicle gel) Absolute numbers not reported Seborrhoeic reported were treatmentrelated adverse effects occurring in 1% or more of people [18] 459 people with seborrhoeic Proportion of people with application site reaction, 4 weeks.4% with ketoconazole (2% gel) 1.7% with placebo (vehicle gel) Absolute numbers not reported reported were treatmentrelated adverse effects occurring in 1% or more of people [18] Successful treatment was defined as both an erythema and scaling score of (none) if the baseline score was 2 or less (moderate) or a score of 1 or less (mild) if the baseline score was 3 (severe) based on a 4point scale for erythema and scaling, and an Investigator's Global Assessment score of (clear) or 1 (almost clear), based on a 5point scale measured at day 28. Comment: See comment on ketoconazole for seborrheoic of the scalp, p 3. OPTION BIFONAZOLE For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. Bifonazole cream may improve skin symptoms in adults with seborrhoeic of the face and body. Benefits and harms Bifonazole versus placebo: We found no systematic review. We found one. [19] Bifonazole cream compared with placebo Bifonazole cream may be more effective at improving symptoms and response to treatment at 4 weeks in people with seborrhoeic of the face (lowquality evidence). [19] 1 people with seborrhoeic of the face Proportion of people classed as healed, 4 weeks 16/37 (43%) with bifonazole 1% cream 1/43 (23%) with placebo Overall P value for healing, improvement, and treatment failure =.44 P values for individual outcomes not reported Bifonazole cream BMJ Publishing Group Ltd 21. All rights reserved

20 [19] 1 people with seborrhoeic of the face Global improvement graded on a 4point scale from = no improvement or worsening to 3 = healing Proportion of people classed as improved, 4 weeks 2/37 (54%) with bifonazole 1% cream 26/43 (61%) with placebo Seborrhoeic Overall P value for healing, improvement, and treatment failure =.44 P values for individual outcomes not reported Bifonazole cream Global improvement graded on a 4point scale from = no improvement or worsening to 3 = healing [19] 1 people with seborrhoeic of the face Rate of treatment failure, 4 weeks 1/37 (3%) with bifonazole 1% cream 7/43 (16%) with placebo Overall P value for healing, improvement, and treatment failure =.44 P values for individual outcomes not reported Bifonazole cream Global improvement graded on a 4point scale from = no improvement or worsening to 3 = healing [19] 1 people with seborrhoeic of the face Proportion of people with a minor adverse effect, 4 weeks 5/5 (1%) with bifonazole 1% cream P value not reported 2/5 (4%) with placebo Minor adverse effects included itch, burning, tightness, erythema, papules, and scaling Comment: OPTION None. TOPICAL CORTICOSTEROIDS (HYDROCORTISONE, BETAMETHASONE VALERATE, CLO BETASONE BUTYRATE, MOMETASONE FUROATE, CLOBETASOL PROPIONATE) For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. In adults with seborrhoeic of the face and body, short courses of topical corticosteroids are considered effective if used episodically, although we found no studies that assessed this. We found no direct information from s about whether topical corticosteroids (hydrocortisone, betamethasone valerate, clobetasone butyrate, mometasone furoate, or clobetasol propionate) are better than no active treatment for seborrhoeic of the scalp in adults. BMJ Publishing Group Ltd 21. All rights reserved.... 2

21 Benefits and harms Topical corticosteroids versus placebo: We found no systematic review or s comparing topical corticosteroids (hydrocortisone, betamethasone valerate, clobetasone butyrate, mometasone furoate, or clobetasol propionate) versus placebo in adults with seborrhoeic of the face and body. Seborrhoeic Comment: Although we found no s of topical corticosteroids in adults with seborrhoeic of the face or body, consensus regards their use as effective. It is current practice to use short courses of topical corticosteroids episodically in seborrhoeic. Affected areas of the body are treated with short courses of potent topical corticosteroids (betamethasone valerate [.1%], mometasone furoate [.1%]) while the face is treated with short courses of moderate (clobetasone butyrate [.5%]) or low potency (hydrocortisone [1%]) corticosteroids. OPTION EMOLLIENTS For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether emollients improve lesions compared with no treatment. We found no direct information from s about whether emollients are better than no active treatment in adults with seborrhoeic of the face and body. Benefits and harms Emollients versus no treatment: We found no systematic review or s of sufficient quality comparing emollients versus no treatment in adults with seborrhoeic of the face and body. Comment: None. OPTION LITHIUM SUCCINATE For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether topical lithium succinate improves lesions compared with no treatment. We found no direct information from s about whether lithium succinate is better than no active treatment in adults with seborrhoeic of the face and body. Benefits and harms Lithium succinate versus placebo: We found no systematic review or s of sufficient quality comparing lithium succinate versus placebo in adults with seborrhoeic of the face and body (see comment). BMJ Publishing Group Ltd 21. All rights reserved

22 Comment: Seborrhoeic We found one crossover (3 people with seborrhoeic of the face, trunk, or both), which compared lithium succinate 8% cream versus placebo. [2] It found that lithium succinate significantly improved symptoms (graded on a 1mm scale on severity of redness, scaling, greasiness, and overall clinical impression of the condition) compared with placebo (results not precrossover). However, these results should be interpreted with caution because of the potential for persistence of effects after crossover. The also had a high withdrawal rate (37%) and it is not clear whether the analyses were conducted on an intention to treat basis. Withdrawals were owing to noncompliance (2 people with lithium succinate, 3 with placebo), local stinging sensation and erythema (1 person with lithium succinate, 2 with placebo), worsening of acne vulgaris (1 person with lithium succinate, 1 with placebo), or resolution of lesions (1 person, group not reported). OPTION SELENIUM SULPHIDE For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether selenium sulphide is beneficial. We found no direct information from s about whether selenium sulphide is better than no active treatment in adults with seborrhoeic of the face and body. Benefits and harms Selenium sulphide versus placebo: We found no systematic review or s. Comment: None. OPTION TERBINAFINE For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether terbinafine is beneficial. We found no direct information from s about whether terbinafine is better than no active treatment in adults with seborrhoeic of the face and body. Benefits and harms Terbinafine versus placebo: We found no systematic review or s. BMJ Publishing Group Ltd 21. All rights reserved

23 Comment: None. OPTION TOPICAL CALCINEURIN INHIBITORS (PIMECROLIMUS, TACROLIMUS) For GRADE evaluation of interventions for Seborrhoeic, see table, p 27. We don't know whether topical calcineurin inhibitors are beneficial in the treatment of seborrhoeic of the face. Benefits and harms Seborrhoeic Topical calcineurin inhibitors versus placebo: We found no systematic review. We found one comparing pimecrolimus cream 1% versus placebo for the treatment of facial seborrhoeic. [21] Pimecrolimus compared with placebo We don't know whether pimecrolimus cream 1% is more effective at improving symptoms (scaling and erythema) and response to treatment at 4 weeks in people with seborrhoeic of the face (very lowquality evidence). Global severity [21] 96 people with seborrhoeic of the face; 96% men, mean age 59 years Change from baseline in total target area score, 4 weeks 3.7 with pimecrolimus cream 1% 3.3 with vehicle cream (placebo) Intentiontotreat (47 people in each group) People in the vehicle group had milder disease at baseline in mean scale target score. See further informa tion on studies for details Total target area was calculated as the sum of the erythema and scaling scores assessed on a 7 point scale. See further information on studies for details P =.191 The difference between groups favoured pimecrolimus on per protocol : for full details see further information on studies Not significant Scaling [21] 96 people with seborrhoeic of the face; 96% men, mean age 59 years Change from baseline in scaling, 4 weeks 1.9 with pimecrolimus cream 1% 1.7 with vehicle cream (placebo) People in the vehicle group had milder disease at baseline in mean scale target score. See further information on studies for details Intentiontotreat (47 people in each group) Erythema was graded on a 4 point scale. See further information on studies for details Erythema [21] 96 people with seborrhoeic of the face; 96% men, mean age 59 years Change from baseline in erythema, 4 weeks 1.8 with pimecrolimus cream 1% 1.6 with vehicle cream (placebo) Intentiontotreat (47 people in each group) Erythema was graded on a 4 point scale. See further information on studies for details BMJ Publishing Group Ltd 21. All rights reserved

24 [21] 96 people with seborrhoeic of the face; 96% men, mean age 59 years People in the vehicle group had significantly milder disease at baseline in mean scaling target score. See further information on studies for details Proportion of people with at least one adverse effect, 4 weeks 47% with pimecrolimus cream 33% with placebo Absolute numbers not reported Intentiontotreat (47 people in each group) Most frequent drugrelated adverse effects were local, mild, and transient skin reactions Seborrhoeic [21] Erythema of the target area on the face was graded using a 4point scale of: = none; 1 = mild, faint red; 2 = moderate, dull red; or 3 = severe, bright red. Scaling of the target area of the face was scored using a 4 point scale of: = none; 1 = mild, up to 1% of lesion; 2 = moderate, >1% to 5% of lesion; or 3 = severe, >5% of the lesion. The total target area score was the sum of the erythema and scaling target area scores ( 6 scale). Results from per protocol The found in a per protocol that pimecrolimus cream 1% significantly improved total target area score compared with vehicle cream (change from baseline in total area score measured on a 6point scale: 3.9 with pimecrolimus v 3.2 with vehicle; P =.156). Per protocol included 41 people in the pimecrolimus and 46 people in the placebo group. Differences in disease at baseline People in the vehicle group had milder disease at baseline in mean scale target score (2.12 with placebo v 2.32 with pimecrolimus; P =.369) and mean facial Investigator's Global Assessment score (2.6 with placebo v 2.9 with pimecrolimus; P =.471). Comment: None. GLOSSARY Lowquality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Moderatequality evidence Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Very lowquality evidence Any estimate of effect is very uncertain. SUBSTANTIVE CHANGES Ketoconazole (scalp) One added comparing ketoconazole 2% versus ciclopirox olamine 1.5% versus placebo. [12] The, which was primarily set up to assess the effectiveness of ciclopirox olamine, found that ketoconazole reduced scaling, itching, erythema, and global severity compared with placebo. Categorisation unchanged (Beneficial). Topical calcineurin inhibitors (pimecrolimus, tacrolimus) One added of pimecrolimus cream 1% for the treatment of facial seborrhoeic, which found no significant difference between groups on intentiontotreat, although pimecrolimus cream 1% improved total target area score compared with vehicle cream in a per protocol (P =.156). Categorisation unchanged (Unknown effectiveness). [21] Topical corticosteroids One added comparing clobetasol propionate.5% shampoo applied for 2.5, 5, and 1 minutes versus placebo. The found that clobetasol propionate.5% applied twice weekly for 2.5, 5, or 1 minutes improved total severity score compared with placebo; that clobetasol propionate.5% applied twice weekly for 5 minutes improved erythema and itching compared with placebo; and that clobetasol propionate.5% BMJ Publishing Group Ltd 21. All rights reserved