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British Journal of Dermatology 2003; 148: 402–410.
Guidelines for treatment of onychomycosis D . T . R O B E R T S , W . D . T A Y L O R * A N D J . B O Y L E   Southern General Hospital, Glasgow G51 4TF, U.K.
*James Cook University Hospital, Middlesbrough, Cleveland TS4 3BW, U.K.
 Taunton and Somerset Hospital, Taunton TA1 5DA, U.K.
These guidelines for management of onychomycosis have been prepared for dermatologists onbehalf of the British Association of Dermatologists. They present evidence-based guidance fortreatment, with identification of the strength of evidence available at the time of preparation of theguidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
among sufferers to seek treatment and among medicalpractitioners to institute therapy. However, treatment These guidelines have been prepared for dermatologists is often prescribed without mycological confirmation of on behalf of the British Association of Dermatologists infection, there may be confusion as to whether fungi and reflect the best data available at the time the report isolated on culture are primary or secondary patho- was prepared. Caution should be exercised in interpre- gens, the relative efficacy of different antifungal agents ting the data; the results of future studies may require against different fungi is not completely understood alteration of the conclusions or recommendations in and drugs are often prescribed for inappropriate treat- this report. It may be necessary or even desirable to depart from the guidelines in the interests of specificpatients and special circumstances. Just as adherence to guidelines may not constitute defence against aclaim of negligence, so deviation from them should not Onychomycosis is an infection of the nail apparatus by fungi that include dermatophytes, nondermatophytemoulds and yeasts (mainly Candida species). The toenails are affected in 80% of all cases of onychomy-cosis; dermatophyte infection, mostly due to Trichophy- Onychomycosis is one of the commonest dermatolog- ton rubrum, is the cause in over 90% of cases.5 ical conditions. A large questionnaire survey of 10 000 Onychomycosis is classified clinically as distal and people suggested a prevalence of 2Æ71% in the U.K.1,2 lateral subungual onychomycosis (DLSO), superficial More recent mycologically controlled surveys in Fin- white onychomycosis (SWO), proximal subungual land3 and in the U.S.A.4 indicate a prevalence of onychomycosis (PSO), candidal onychomycosis and between 7 and 10%. Increasing publicity about disease prevalence, and the advent of new and more effectiveantifungal drugs, has led to a greater enthusiasm Distal and lateral subungual onychomycosis DLSO accounts for the majority of cases and is almost always due to dermatophyte infection. It affects the These guidelines were commissioned by the British Association of hyponychium, often at the lateral edges initially, and Dermatologists Therapy Guidelines and Audit subcommittee. Mem- spreads proximally along the nail bed resulting in bers of the committee are N.H.Cox (Chairman), A.V.Anstey, subungual hyperkeratosis and onycholysis although C.B.Bunker, M.J.D.Goodfield, A.S.Highet, D.Mehta, R.H.MeyrickThomas, A.D.Ormerod, J.K.Schofield and C.H.Smith.
the nail plate is not initially affected. DLSO may be Ó 2003 British Association of Dermatologists G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S confined to one side of the nail or spread sideways to and further cuticular detachment, i.e. a vicious circle.
involve the whole of the nail bed, and progresses Infection and inflammation in the area of the nail matrix relentlessly until it reaches the posterior nail fold.
eventually lead to a proximal nail dystrophy.
Eventually the nail plate becomes friable and may Distal nail infection with Candida yeasts is uncom- break up, often due to trauma, although nail destruc- mon and virtually all patients have Raynaud’s phe- tion may be related to invasion of the plate by nomenon or some other form of vascular insufficiency.
dermatophytes that have keratolytic properties. Exam- It is unclear whether the underlying vascular problem ination of the surrounding skin will nearly always gives rise to onycholysis as the initial event or whether reveal evidence of tinea pedis. Toenail infection is an yeast infection causes the onycholysis. Although almost inevitable precursor of fingernail dermatophy- candidal onychomycosis cannot be clinically differen- tosis, which has a similar clinical appearance although tiated from DLSO with certainty, the absence of toenail involvement and typically a lesser degree of subungualhyperkeratosis are helpful diagnostic features.
Chronic mucocutaneous candidiasis has multifacto- rial aetiology leading to diminished cell-mediated SWO is also nearly always due to a dermatophyte immunity. Clinical signs vary with the severity of infection, most commonly T. mentagrophytes. It is much immunosuppression, but in more severe cases gross less common than DLSO and affects the surface of the thickening of the nails occurs, amounting to a Candida nail plate rather than the nail bed. Discoloration is granuloma. The mucous membranes are almost always white rather than cream and the surface of the nail plate is noticeably flaky. Onycholysis is not a common Secondary candidal onychomycosis occurs in other feature of SWO and intercurrent foot infection is not as diseases of the nail apparatus, most notably psoriasis.
Any of the above varieties of onychomycosis may PSO, without evidence of paronychia, is an uncommon eventually progress to total nail dystrophy where the variety of dermatophyte infection often related to inter- nail plate is almost completely destroyed.
current disease. Immunosuppressed patients, notablythose who are human immunodeficiency virus-posit- ive, may present with this variety of dermatophyteinfection; conditions such as peripheral vascular dis- This section follows the criteria set out by Evans and ease and diabetes also may present in this way.
Gentles.6 Treatment should not be instituted on clinical Evidence of intercurrent disease should therefore be grounds alone. Although 50% of all cases of nail dystrophy are fungal in origin it is not always possibleto identify such cases accurately. Treatment needs to beadministered long-term and enough time must elapse for the nail to grow out completely before such Infection of the nail apparatus with Candida yeasts may treatment can be designated as successful. Toenails present in one of four ways: (i) chronic paronychia take around 12 months to grow out and fingernails with secondary nail dystrophy; (ii) distal nail infection; about 6 months. This is far too long to await the results (iii) chronic mucocutaneous candidiasis; and (iv) sec- of therapeutic trial and, in any case, treatment is not always successful. If the diagnosis is not confirmed, and Chronic paronychia of the fingernails generally only improvement does not occur, it is impossible to tell occurs in patients with wet occupations. Swelling of the whether this represents treatment failure or an initial posterior nail fold occurs secondary to chronic immer- incorrect diagnosis. Although the cost of diagnostic sion in water or possibly due to allergic reactions to some tests may be deemed high at times of budgetary foods, and the cuticle becomes detached from the nail constraint, the cost is always small relative to inappro- plate thus losing its water-tight properties. Microorgan- isms, both yeasts and bacteria, enter the subcuticular Laboratory diagnosis consists of microscopy to space causing further swelling of the posterior nail fold visualize fungal elements in the nail sample and Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 culture to identify the species concerned. The success Such dystrophies, notably psoriasis, regularly yield or otherwise of such tests depends upon the quality of Candida yeasts on culture but they are rarely causal in the sample, the experience of the microscopist and the ability of the laboratory to discriminate betweenorganisms that are likely pathogens, organisms grow- ing in the nail as saprophytes, and contamination ofthe culture plate.
Although dermatophyte onychomycosis is relentlessly Given that dermatophyte onychomycosis is primarily progressive there remains a view among some practi- a disease of the nail bed rather than of the nail plate, tioners that it is a trivial cosmetic problem that does not subungual debris taken from the most proximal part of merit treatment. In the elderly the disease can give rise the infection is likely to yield the best results. In DLSO to complications such as cellulitis and therefore further material can be obtained from beneath the nail: a small compromise the limb in those with diabetes or periph- dental scraper is most useful for this purpose. If the nail eral vascular disease. While these complications may is onycholytic then this can be cut back and material not be common they are certainly serious. The high can be scraped off the underside of the nail as well as prevalence of the disease is the result of heavy from the nail bed. As much material as possible should contamination of communal bathing places7 by infec- be submitted to the laboratory because of the relative ted users; disinfecting the floors of such facilities is very paucity of fungal elements within the specimen. In difficult because fungal elements are protected in small SWO the surface of the infected nail plate can be pieces of keratin. It is therefore logical to try to reduce scraped and material examined directly. PSO is rare the number of infected users by effective treatment and and again should be scraped with a scalpel blade.
thus reduce disease prevalence. Finally, onychomycosis However, punch biopsy to obtain a sample of the full is a surprisingly significant cause of medical consulta- thickness of nail together with the nail bed may be necessary. Some of the material obtained is placed on a Onychomycosis should not therefore be considered a glass slide and 20% potassium hydroxide added. Fifteen trivial disease, and there is a sound case for treatment to 20 min should be allowed to elapse before examin- on the grounds of complications, public health consid- ing the sample by direct microscopy. The addition of erations and effect on quality of life.
Parker’s blue ⁄ black ink may enhance visualization ofthe hyphae. An inexperienced observer may very wellmisdiagnose cell walls as hyphae and care should be taken to examine all of the specimen as fungal elements within the material may be very scanty.
The remaining material should be cultured on Both topical and oral agents are available for the Saboraud’s glucose agar, usually with the addition of treatment of fungal nail infection. The primary aim of an antibiotic. The culture plate is incubated at 28 °C treatment is to eradicate the organism as demonstrated for at least 3 weeks before it is declared negative, as by microscopy and culture. This is defined as the primary end-point in almost all properly conducted Direct microscopy can be carried out by the clinician, studies. Clinical improvement and clinical cure are and higher specialist training includes teaching of this secondary end-points based on a strict scoring system technique. However, nail microscopy is difficult and of clinical abnormalities in the nail apparatus. It must should only be carried out by those who do it on a be recognized that successful eradication of the fungus regular basis. Fungal culture should always be carried does not always render the nails normal as they may out in a laboratory experienced in handling mycology have been dystrophic prior to infection. Such dystrophy specimens, because of potential pitfalls in interpretation may be due to trauma or nonfungal nail disease; this is of cultures. It must be remembered that the most particularly likely in cases where yeasts or nondermat- common cause of treatment failure in the U.K. is ophyte moulds (secondary pathogens and saprophytes, incorrect diagnosis, which is usually made on clinical grounds alone. This should not be further compounded Invariably mycological cure rates are about 30% by incorrect laboratory interpretation of results.
better than clinical cure rates in the majority of studies, Histology is almost never required and its use is the clinical cure rates often being below 50%. Publi- usually confined to other causes of nail dystrophy.
cations of clinical trials in onychomycosis are often Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S criticized for quoting mycological cure rates and thus to achieve clinical and mycological cure with topical overemphasizing the efficacy of treatment. While it is nail preparations, these cure rates do not compare understood that the patient is more concerned with favourably with those obtained with systemic drugs.
improvement in the clinical appearance of the nail Currently, topical therapy can only be recommended rather than eradication of the organism, questions for the treatment of SWO and in very early cases of regarding patients’ satisfaction at the end of a study DLSO where the infection is confined to the distal edge usually mirror very closely the mycological cure rate.
This suggests that eradication of the organism does A combination of topical and systemic therapy may restore the nail to its previous state prior to infection improve cure rates still further or possibly shorten the even though that state may not be completely ÔnormalÕ duration of therapy with the systemic agent. Thus far the results of such studies are inconclusive. A study Systemic therapy is almost always more successful comparing terbinafine and amorolfine with terbinafine than topical treatment, which should only be used in alone produced somewhat idiosyncratic results12 and SWO, possibly very early DLSO or when systemic was not properly blinded, so further evidence from well-controlled double-blind studies is required beforecombination therapy can be advocated.
Although there are no studies comparing one topical preparation with another in a properly controlled There are several topical antifungal preparations fashion, it is likely that amorolfine nail lacquer (Loce- available both as prescription-only medicines and on rylÒ) is the most effective preparation of those avail- an over-the-counter basis. The active antifungal agent in these preparations is either an imidazole, an allyl-amine or a polyene, or a preparation that contains a chemical with antifungal, antiseptic and sometimeskeratolytic properties such as benzoic acid, benzyl The three drugs currently licensed for general use in peroxide, salicylic acid or an undecenoate. Products onychomycosis are listed in Table 2. The two other that are specifically indicated for nail infection are systemic agents available for oral use, ketoconazole and available as a paint or lacquer that is applied topically.
fluconazole, are not licensed for nail infection. Ketocon- There are four such preparations (Table 1).
azole may be used in some recalcitrant cases of yeast There are no published studies on the efficacy of infection affecting the nails but cannot be prescribed for salicylic acid (PhytexÒ; Pharmax, Bexley, U.K.) and dermatophyte onychomycosis because of problems with methyl undecenoate (MonphytolÒ; LAB, London, U.K.) hepatotoxicity. The use of fluconazole thus far has in fungal nail infection and their use cannot be concentrated on vaginal candidiasis and systemic yeast infections although it is active against dermatophytes.
Amorolfine (LocerylÒ; Galderma, Amersham, U.K.) There are some published studies of its use in nail nail lacquer has been shown to be effective in around infection but the dose and duration of treatment are 50% of cases of both fingernail and toenail infection in not yet clear and it is not licensed for this indication in a large study where only cases with infections of the the U.K., nor does it appear likely to be so in the near distal portion of the nail were treated.10 There are several published studies examining the efficacy oftioconazole (TrosylÒ; Pfizer, Sandwich, U.K.) nail solu- Griseofulvin. Griseofulvin (FulcinÒ; GrisovinÒ; Glaxo- tion, with very variable results ranging from cure rates SmithKline, Uxbridge, U.K.) is weakly fungistatic, and of around 20% up to 70%.11 While it is clearly possible acts by inhibiting nucleic acid synthesis, arresting cell Table 1. Topical agents for onychomycosis, with strength of recommendation and quality of evidence grading Strength of recommendation and quality of evidence Amorolfine (LocerylÒ; Galderma, Amersham, U.K.) nail lacquer Strength of recommendation B, Quality of evidence II-ii Tioconazole (TrosylÒ; Pfizer, Sandwich, U.K.) nail solution Strength of recommendation C, Quality of evidence II-iii Salicylic acid (PhytexÒ; Pharmax, Bexley, U.K.) paint Strength of recommendation E, Quality of evidence IV Undecenoates (MonphytolÒ; LAB, London, U.K.) paint Strength of recommendation E, Quality of evidence IV Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 division and inhibiting fungal cell wall synthesis.13–15It is available in tablet form and is the only antifungal agent licensed for use in children with onychomycosis,with a recommended dose for age groups of 1 month and above of 10 mg kg)1 daily. It requires to be taken with fatty food to increase absorption and aid bioavail- ability. In adults the recommended dose is 500 mgdaily given for 6–9 months in fingernail infection and 12–18 months in toenail infection. Mycological curerates in fingernail infection are reasonably satisfactory at around 70% but griseofulvin is a disappointing drug in toenail disease where cure rates of only 30–40% can It is generally recognized that 500 mg daily is too small a dose for nail infection and 1 g daily is most often prescribed, but there is no certain evidence that this improves cure rates in toenail infection. Although the cost of griseofulvin is very low, its poor cure rate, often necessitating further treatment, suggests that its ⁄ efficacy ratio is relatively high. Both direct and historical comparison with studies of the newer anti- fungal agents terbinafine17–19 and itraconazole20–22 suggest that griseofulvin is no longer the treatment of choice for dermatophyte onychomycosis.
Side-effects include nausea and rashes in 8–15% of patients. In adults, it is contraindicated in pregnancy and the manufacturers caution against men fathering Terbinafine. Terbinafine (LamisilÒ; Novartis, Camber- ley, U.K.), an allylamine, inhibits the enzyme squalene epoxidase thus blocking the conversion of squalene to squalene epoxide in the biosynthetic pathway of ergosterol, an integral component of the fungal cell wall.23 Its action results in both a depletion of ergosterol, which has a fungistatic effect, together with an accumulation of squalene, which appears to be directly fungicidal. The minimum inhibitory concen- tration (MIC) of terbinafine is very low, approximately 0Æ004 lg mL)1. This is equivalent to the minimal fungicidal concentration (MFC), demonstrating that this drug is truly fungicidal in vitro. It is the most active currently available antidermatophyte agent in vitro and clinical studies strongly suggest that this is also the Itraconazole. Itraconazole (SporonoxÒ; Janssen-Cilag, High Wycombe, U.K.) is active against a range of fungi including yeasts, dermatophytes and some nonder-matophyte moulds. It is not as active in vitro against dermatophytes as terbinafine, its MIC being 10 times Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S greater. Although it is generally felt to be a fungistatic therapy. The first compared terbinafine 250 mg daily for 16 weeks with four ÔpulsesÕ of itraconazole 400 mg although its MFC is about 10 times higher than its daily for 1 week in every 4 weeks for 16 weeks and also with terbinafine 500 mg daily for 1 week in Both terbinafine and itraconazole persist in the nail every 4 weeks for 16 weeks.30 As only approximately for a considerable period after elimination from the 20 patients were recruited in each study group, this plasma.26 This property has given rise to a novel was a very small study; the regimens used were not intermittent (ÔpulsedÕ) treatment regimen using itrac- those of the U.K. product licences, and the results comparing the groups were not significantly different.
A more recent and much larger study has been Terbinafine vs. itraconazole in dermatophyte onychomyco- completed comparing terbinafine 250 mg daily for sis. Both of these drugs have been shown to be more both 3 and 4 months with itraconazole 400 mg daily effective than griseofulvin in dermatophyte onychomy- for 1 week · 3 and 1 week · 4. One hundred and cosis and therefore the optimum choice of treatment twenty patients were recruited to each group and lies between terbinafine and itraconazole.
the follow-up period was 72 weeks.31 The study Terbinafine is licensed at a dose of 250 mg daily for was carried out in double-blind, double-placebo fash- 6 weeks and 12 weeks in fingernail and toenail infec- ion and demonstrated terbinafine 250 mg daily for tion, respectively. Itraconazole is licensed at a dose of both 3 and 4 months to be very significantly superior 200 mg daily for 12 weeks continuously, or alternat- to both three and four ÔpulsesÕ of itraconazole (Strength ively at a dose of 400 mg daily for 1 week per month. It is recommended that two of these weekly courses, 21 days apart, are given for fingernail infections and The 151 patients in the Icelandic arm of this study were further studied for long-term effectiveness of There have been numerous open and placebo-con- treatment during a 5-year blinded prospective follow- trolled studies of both drugs in dermatophyte nail up study.32 At the end of the study mycological cure infection. However, historical comparisons of such without a second therapeutic intervention was found studies do not provide evidence of equivalent quality in 46% of the 74 terbinafine-treated subjects but in as that achieved by directly comparative double-blind only 13% of the 77 itraconazole-treated subjects.
trials, as even in properly conducted studies the results Mycological and clinical relapse was significantly can be influenced by variation in the criteria for higher in the itraconazole group (53% and 48%) than mycological or clinical cure, or by the period of follow- the terbinafine group (23% and 21%) (Strength of up. It is generally accepted that patients entered into recommendation A, Quality of evidence I).
such studies should be both microscopy- and culture- The superiority of terbinafine has recently been positive for fungus and that mycological cure should be supported by a systematic review of oral treatments defined as microscopy and culture negativity at com- for toenail onychomycosis;33 this reference documents pletion. Clinical criteria for cure are difficult to interpret many additional studies and also the varied and often as the appearance of the nail prior to infection is incompletely presented criteria that have been used to generally unknown and, especially in the case of toenails, because trauma can affect their appearance.
Short follow-up periods after cessation of therapy are unlikely to allow interpretation of which is the superiordrug; a follow-up period of at least 48 weeks (prefer- Most yeast infections can be treated topically, partic- ably 72 weeks) from the start of treatment should be ularly those associated with paronychia. Antiseptics allowed both in order to allow the most effective can be applied to the proximal part of the nail and preparation to become apparent and to identify relapse allowed to wash beneath the cuticle, thus sterilizing the subcuticular space. Ideally, such antiseptics should be There are various published studies comparing ter- broad spectrum, colourless and nonsensitizing. They binafine with continuous itraconazole therapy,27–29 require to be applied until the integrity of the cuticle most of which demonstrate terbinafine to be the more has been restored, which may be several months. An effective agent. Thus far there are only two studies imidazole lotion alternating with an antibacterial lotion comparing terbinafine with intermittent itraconazole Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 Itraconazole (SporonoxÒ) is the most effective agent Cure rates, both short- and long-term, may be for the treatment of candidal onychomycosis where the influenced by correction of associated orthopaedic nail plate is invaded by the organism.34 It is used in the and podiatric factors to avoid, as much as possible, same dosage regimen as for dermatophytes, i.e.
trauma that particularly affects the great toenails.
400 mg daily for 1 week per month repeated for2 months in fingernail infection. Candida infection of toenails is much less common but can be treated asabove using three or four pulses.
1 Treatment should not be commenced before myco- 2 Dermatophytes are by far the commonest causal Many varieties of saprophytic moulds can invade 3 Culture of yeasts and nondermatophyte moulds diseased nail. Scopulariopsis brevicaulis is the common- should be interpreted carefully in each individual est of these and may be a secondary pathogen. Its case. In the majority, yeasts are likely to be a response to systemic antifungal agents is variable, secondary infection and nondermatophyte moulds to although terbinafine is probably the drug of choice in be saprophytic in previously damaged nails.
that the primary nail disease is quite likely to be a 4 Topical treatment is inferior to systemic therapy in dermatophyte infection that is masked by the Scopu- all but a small number of cases of very distal lariopsis. There is little categorical evidence to support the choice of one drug.35 In the U.S.A. and Europe 5 Terbinafine is superior to itraconazole both in vitro cyclopirox nail lacquer has its advocates but it is not and in vivo for dermatophyte onychomycosis, and available in the U.K. Nail avulsion followed by an oral should be considered first-line treatment, with itrac- agent during the period of regrowth is probably the best onazole as the next best alternative.
method of restoring the nail to normal.
6 Cure rates of 80–90% for fingernail infection and 70–80% for toenail infection can be expected. Incases of treatment failure the reasons for such failure should be carefully considered. In such cases either Although terbinafine is demonstrably the most effective an alternative drug or nail removal in combination agent in dermatophyte onychomycosis a consistent with a further course of therapy to cover the period failure rate of 20–30% is found in all studies. If the most obvious causes of treatment failure, notably poorcompliance, poor absorption, immunosuppression, der- matophyte resistance and zero nail growth are exclu-ded, the commonest cause of failure is likely to be 1 Has a positive culture been obtained before com- kinetic.36 Subungual dermatophytoma has been des- mencing systemic therapy for onychomycosis? cribed37 and it is likely that this tightly packed mass of 2 Has an appropriate agent been chosen, based on the fungus prevents penetration of the drug in adequate concentrations. In such cases partial nail removal is 3 Are arrangements in place for adequate duration of indicated. It is been demonstrated that cure rates of treatment to be supplied from hospital or general close to 100% can always be achieved if all affected nails are avulsed under ring block prior to commence- 4 Has immunosuppression been considered in cases of ment of treatment. However, this is neither feasible nor necessary in most cases and the best approach is to tryto identify those individual nails that are likely to fail Reports of long-term follow-up of treated patients David T.Roberts is a member of the Dermatology have recently been presented, suggesting that positive Advisory Board of Novartis Pharmaceuticals Ltd. He mycology at 12 and 24 weeks after commencement of has given advice to almost all other manufacturers of therapy are poor prognostic signs and may indicate a antifungal agents and has spoken at symposia organ- need for retreatment or for a change of drug. However, ized by a number of these companies. The other authors have no conflict of interest.
Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 G U I D E L I N E S F O R T R E A T M E N T O F O N Y C H O M Y C O S I S 23 Ryder NS, Favre B. Antifungal activity and mechanism of action of terbinafine. Rev Contemp Pharmcother 1997; 8: 275–88.
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21 Korting HC, Schafer-Korting M, Zienicke H et al. Treatment of tinea unguium with medium and high doses of ultramicrosizegriseofulvin compared with that with itraconazole. Antimicrob The consultation process and background details for Agents Chemother 1993; 37: 2064–8.
the British Association of Dermatologists guidelines 22 Cribier BJ, Paul C. Long-term efficacy of antifungals in toenail onychomycosis: a critical review. Br J Dermatol 2001; 145: 446– Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410 Evidence obtained from well-designed controlled A There is good evidence to support the use of the II-ii Evidence obtained from well-designed cohort or case-control analytical studies, preferably from B There is fair evidence to support the use of the more than one centre or research group.
II-iii Evidence obtained from multiple time series with C There is poor evidence to support the use of the or without the intervention. Dramatic results in uncontrolled experiments (such as the introduc- D There is fair evidence to support the rejection of the tion of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
E There is good evidence to support the rejection of the Opinions of respected authorities based on clinical experience, descriptive studies or reports of expertcommittees.
Evidence inadequate owing to problems of meth- odology (e.g. sample size, or length or compre- hensiveness of follow-up or conflicts of evidence).
designed, randomized controlled trial.
Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 402–410

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