ARTICLE
Auteur(s) : Eggert Stockfleth, Helmut
Kerl
Department of Dermatology, Venerology and Allergology, Charité
Campus Mitte,Universität Berlin Charitéplatz 1, 10117 Berlin,
Germany
These guidelines have been accepted by the UEMS and should
facilitate the management of actinic keratoses Europe-wide. They
are intended to provide an important resource for improving the
quality of care.These guidelines attempt to cover clinical practice
across Europe and should be regarded as a set of suggestions for
care delivery.The guidelines have also been published on the
website of the EDF (www.euroderm.org), where periodical updates
will be made. The copyright of these guidelines remains at the
EDF.Chairman of EDF Guideline Committee:Prof. Dr. Wolfram Sterry,
Berlin (Germany)Subcommittee Members:Prof. Dr. Eggert Stockfleth,
Berlin (Germany)Prof. Dr. Helmut Kerl, Graz (Austria)Prof. Dr.
Lasse R. Braathen, Bern (Switzerland)Dr. Rino Cerio, London
(UK)Prof. Dr. Bernard Cribier, Strasbourg (France)Prof. Dr. Carlos
Ferrándiz Foraster, Badalona (Spain)Prof. Dr. Alberto Giannetti,
Modena (Italy)Prof. Dr. Laios Kemény, Szeged (Hungary)Prof. Dr.
Bernt Lindelöf, Stockholm (Sweden)Prof. Dr. Martino Neumann,
Rotterdam (The Netherlands)Prof. Dr. Wolfram Sterry, Berlin
(Germany)Members of EDF Guideline Committee:Prof. Dr. Werner
Aberer, Graz (Austria)Prof. Dr. Martine Bagot, Créteil
(France)Prof. Dr. Lasse Braathen, Bern (Switzerland)Prof. Dr.
Sergio Chimenti, Rome (Italy)Prof. Dr. José Luis Diaz-Perez, Bilbao
(Spain)Prof. Dr. Vladimir Hegyi, Bratislava (Slovak Republic)Prof.
Dr. Lajos Kemény, Szeged (Hungary)Prof. Dr. Gillian Murphy, Dublin
(Ireland)Prof. Dr. Martino Neumann, Rotterdam (The
Netherlands)Prof. Dr. Tony Ormerod, Aberdeen (UK)Prof. Dr. Annamari
Ranki, Helsinki (Finland)Prof. Dr. Fenella Wojnarowska, Oxford
(UK)List of conflicts of interest:Prof. Dr. Helmut Kerl, Graz
(Austria) is a consultant for 3M PharmaceuticalsProf. Dr. Wolfram
Sterry, Berlin (Germany) is a consultant for 3M
PharmaceuticalsProf. Dr. Bernard Cribier, Strasbourg (France) is a
speaker of symposia sponsored by ShireProf. Dr. Eggert Stockfleth,
Berlin (Germany) is a speaker for 3M Pharmaceuticals, Shire,
Galderma
Guidelines for the management of actinic keratoses
These guidelines are based on a previous document prepared by E.
Stockfleth et al. prepared for the German “Arbeitsgemeinschaft
Dermatologische Onkologie – Deutsche Krebsgesellschaft” and have
been modified by the Guidelines Committee of the European
Dermatology Forum. They reflect the data available at the time the
report was written. Future studies may require alterations of the
conclusions or recommendations in this report.
The level of evidence of published studies is based on the
criteria from Sackett
(http://www.cebm.net/levels_of_evidence.asp).
Disclaimer
These guidelines for the management of actinic keratoses (AK) have
been prepared by the AK subcommittee of the Guidelines Committee of
the European Dermatology Forum. They represent an evidence-based
guidance for treatment for actinic keratoses, with identification
of the level of evidence available at the time of preparation, and
contain a brief overview of epidemiological aspects and clinical
management of patients with AK.
A variety of different and well-accepted therapeutic modalities
are used in the management of AK. These guidelines aim to aid in
the selection of the most appropriate treatment option for
individual patients.
Definition and pathogenesis
Actinic keratoses (AKs) are defined as keratotic macules, papules
or plaques with superficial scale on a red base, occurring on areas
of extensive damage through sunlight. They should be classified as
in situ squamous cell carcinomas (SCC) [1, 2]. Histopathologically
an intraepidermal proliferation of atypical keratinocytes can be
observed.
AKs are mainly caused by non-ionising radiation, especially
through ultraviolet light associated with chronic sun exposure.
While UV-A (320-400 nm) induced photooxidative stress indirectly
induces characteristic DNA mutations, the spectrum of UV-B (290-320
nm) irradiation directly results in the formation of cyclobutane
(thymin) dimer formation and C → T or CC → TT transitions in DNA
and RNA. In the absence of appropriate repair mechanisms, these DNA
changes represent the initiation of keratinocyte mutations which
can progress into the development of AKs [3]. Other factors like
repeated iatrogenic exposure to UV-A with or without combination
with psoralenes, X-rays or radioisotopes are known to induce AKs.
Human papilloma-viruses (HPV) play a role as co-carcinogen in the
ethiopathogenesis of AKs [4, 5]. The association between cutaneous
HPV types and skin carcinogenesis is well known since 1978 in
patients with epidermodysplasia verruciformis [6]. In AKs often
cutaneous HPV types and rarely genital types have been detected
[7]. Tumour-inducing effects have been also be shown for viral E6
protein of cutaneous HPVs. E6 interacts with pro-apoptotic
Bak-protein and therefore inhibits apoptosis [8, 9]. Other factors
include the skin phototype of the individual, genetic factors,
chronic immunosuppression, history of arsenic exposure.
AKs can occur as a single lesion or affect an entire field such
as sun exposed areas on the forehead or the back of the hand (syn.
field cancerisation) [10]. Cancer-related molecular alterations are
found in both AK and SCC. This genetic link supports the malignant
nature of AKs from their inception. The transformed keratinocytes
show a high mutation rate of the tumour-suppressor gene p53 and
expression of telomerase [11, 12]. Additionally, similar
chromosomal aberrations have been described for invasive SCC
typical and AK [13].
Epidemiology
Epidemiological data show a high occurrence rate of AKs in
populations with skin phototype I-III and an increase of AKs in the
last decades, worldwide. Regions with higher UV exposure have a
higher prevalence of AKs. In Europe a prevalence of 15% in men and
6% in women has been documented in a recent report from the U.K.
Over the age of 70 years, 34% of males and 18% of females were
found to have AKs [14]. The USA show prevalences between 11-26%
[15], and in Australia (Queensland) a very high prevalence of AKs
(55% of men between 30-70 years showed AKs, as opposed to 37% of
women) has been reported [16].
In addition to sex, gender and age, other risk factors are
known. Geographical factors such as altitude and latitude,
increased vacational and recreational sun exposure, a history of
severe sunburns in childhood, genetic disorders (xeroderma
pigmentosum), and immunodeficiency contribute to the development of
actinic keratoses. Clinically, the affected individual often
presents with the characteristic signs of dermatoheliosis such as
freckles, solar lentigines and rhytides. High-risk-AKs occur mainly
in immunosuppressed patients [17]. Organ-transplanted patients have
a 250 fold higher risk of developing AKs and a 100 fold higher risk
of developing invasive SCCs [18, 19]. While about 40% of
immunosuppressed patients develop an invasive SCC only
approximately 10% (6-16%) of immunocompetent patients with AKs show
this progression [20, 18].
In conclusion, the incidence of AKs is increasing such that
millions of patients are affected worldwide, making actinic
keratoses the most frequent carcinoma in situ in man.
Clinical aspects
Typical AKs are skin-coloured to reddish-brown scaly macules,
papules or plaques occurring in areas of chronic sun exposure,
especially on the face, forehead, scalp, ears, neck, décolleté,
arms, dorsum of the hands, and lower lips.
Lesions size ranges from a few millimetres up to 2 centimetres
or more in diameter. AKs rarely develop as solitary lesions; in
fact multiple lesions are commonly present (field
cancerisation).
A clinical classification is illustrated in table 1( Table 1 ).
No distinct clinical boundaries exist between AKs and SCC. It
has been reported that before AKs progress to invasive SCC, they
may become inflamed and painful [21].
Diagnosis of AKs is based upon the typical clinical aspects.
Histological confirmation is necessary, when clinical doubts
exist or when special forms of treatment are considered. A biopsy
which includes the dermis is required if deeper involvement needs
to be excluded.
Dermoscopy can be helpful in the differential diagnosis of
pigmented actinic keratosis vs. lentigo maligna melanoma and
superficial and/or pigemented basal-cell carcinoma.
Other techniques, including confocal scanning laser microscopy,
have been utilised in serial clinical investigations [22].
Table 1 Clinical classification*
|
- keratotic
|
|
- atrophic
|
|
- cornu cutaneum
|
|
- verrucous
|
|
- pigmented
|
|
- lichenoid
|
Histopathology
The histological criteria of AKs are summarized in table 2( Table 2 ).
The lichenoid subtype of AK is accompanied by dense bandlike
infiltrates of lymphocytes in the stratum papillare. Acantholytic
dyskeratotic cells above suprabasal clefts are found in
acantholytic AKs. The degree of intraepidermal involvement by
keratinocytic atypia is graded as mild (AK I), moderate (AK II) or
severe (AK III).
The classification of AKs takes into consideration that AK is an
early stage of cancer and that both AKs and SCC are stages in the
evolution of a continuous process characterised by the
proliferation of atypical keratinocytes.
On histopathologic grounds alone, AK and SCC are
indistinguishable in the epidermal layer, and AKs fulfill all
criteria for SCC. Both contain atypical keratinocytes with loss of
polarity, nuclear pleomorphism, disordered maturation, and
increased numbers of mitotic figures [1]. AK and SCC are frequently
contiguous with one another. It is important to emphasize that in a
study of > 1000 SCC on sun-damaged skin nearly 100% of these
lesions contained histopathologic changes of AK at the periphery
[23].
Table 2 Histopathological features
|
Early lesions
|
|
- Focally atypical keratinocytes (large pleomorphic nuclei,
hyperchromatic nuclei) in the basal layer of the epidermis
|
|
- Crowding of nuclei
|
|
- Alternation of ortho- and parakeratosis
|
|
- Actinic elastosis
|
|
Fully developed lesions
|
|
- Hyperplasia (or sometimes atrophy) of the epidermis
|
|
- Rete ridges arranged in buds or columns
|
|
- Alternation of ortho- and parakeratosis
|
|
- Neoplastic cells spare both acrosyringia and acrotrichia
|
|
- Atypical epidermal keratinocytes involve mostly the lower half of
the epidermis. Sometimes with focal involvement of the entire
thickness of the epidermis
|
|
- Atypical keratinocytes extend along adnexal epithelia
|
|
- Dyskeratotic cells and mitotic figures
|
|
- Actinic elastosis
|
|
- Lymphocytic infiltrate of variable density
|
Treatment options
Overview
It is impossible to predict which AK will become thicker or more
invasive with a potential for destructive growth and risk for
metastases, i.e. develop into metastatic squamous cell carcinomas.
AKs should therefore be treated.
In the decision which therapy should be chosen the following
factors play a major role: duration and course of lesions,
localisation and extent of disease, solitary or multiple AKs, age,
and co-morbidity, mental condition and compliance of the patient,
pre-existing (skin) cancer and as well as the presence of other
risk factors (especially immuno-suppression).
When considering treatment options for actinic keratoses, there
is a great variety of accepted methods. When using non-surgical
treatment modalities an exemplary probe biopsy for histological
diagnosis may be indicated before therapy.
The following treatment options are not listed in a ranked
order.
Surgical excision, dermabrasion and curettage
Excision of AKs is not routinely used and only chosen if invasive
SCC is suspected or recurrent lesions are present.
Shave excision is frequently used for AK. Sutures are not
necessary and a histologic diagnosis can be provided [24].
Similarly, curettage may be used alone or in conjunction with
electro-surgery or cryotherapy with excellent cure rates [25].
Curettage may also be combined with zinc chloride as Schreus-method
which is also a very effective method for the treatment of field
cancerisation [26].
Dermabrasion is especially useful for larger areas of AK on the
scalp [27].
All these methods require local anesthesia and may leave
epidermal changes or scarring.
Cryotherapy
Cryotherapy is the most common treatment for AKs, especially for
the management of multiple AKs [25, 28, 29]. Cryotherapy is
available in techniques using liquid nitrogen or as spray or
contact-cryotherapy. Field cancerisation, which describes a
chronically sun-damaged area can be treated by cryo-peeling [30].
Cryotherapy is not standardised concerning frequency, duration,
intensity and definitive specification of temperature in the frozen
tissue. As a non-specific technique, cryotherapy destroys atypical,
but also normal cells by disruption and separation of the epidermis
from the dermis. Pain, redness, edema and blistering can occur
during and after treatment. Scarring and hypo- or hyperpigmentation
is commonly observed.
Though cryotherapy is often used, controlled studies are
missing. Complete responses differ from 75% to 98% ([31] - level
of evidence 2b, [32] - level of evidence 3a); the
recurrence rates of AKs have been estimated from 1.2% to 12% within
a 1-year follow up period ([30] - level of evidence 3a, [33]
- level of evidence 3b].
Chemical peeling
Chemical peeling is a destructive method through the application of
caustic agents like trichloroacetic acid, alpha-hydroxy acids,
zinc-chloride or phenolic acid. Chemical peeling can be a useful
alternative for treatment of extensive facial AK ([34] - level
of evidence 2c). The efficacy of chemical peelings depends on
the agent used and is quoted to be round about 75%; recurrence
rates are from 25-35% within one year after therapy. Side effects
of chemical peelings include pain, inflammation, pigmentary
alterations, and the risk of scarring ([35] - level of evidence
2c, [36, 37] - level of evidence 3b).
Laser
Near infrared laser systems like carbon dioxide (CO2) or Erbium-YAG
lasers are indicated in special cases for AKs. Both are ablative
laser systems and can be used for single lesions as well as full
face resurfacing. Full face laser resurfacing provides long-term
effective prophylaxis against AKs and may reduce the incidence of
AKs related SCC [38]. Adverse events are pain, inflammation,
pigmentary changes and scarring as well as delayed healing and
postinflammatory erythema. Although complete remission is
documented from 90 to 91% recurrence rates for single lesions range
from 10 to 15% within 3 to 6 months ([39] - level of evidence
3b, [40]). Disappointing results reported in earlier literature
maybe related to technical aspects, as the outcomes of full face
resurfacing are strongly user dependent. [41]. The expert opinion
is that in skilled hands there is a place for CO2/Erbium-YAG laser
in the management for AKs and the treatment of actinic cheilitis.
Radiotherapy
The treatment of AKs with X-rays is considered obsolete due to the
co-carcinogenic effect of X-rays.
Photodynamic therapy
Topical photodynamic therapy (PDT) acts through the selective
destruction of atypical keratinocytes (depth of penetration
3-4 mm) through light activation of a photosensitiser in the
presence of oxygen. The neoplastic cells accumulate more
photosensitiser than normal cells. The photosensitiser generates
reactive oxygen species upon illumination, which results in
selective photochemical and photothermal effects on the irradiated
tissue. The most commonly used precursors of protoporphyrin IX are
5-aminolevulinic acid (ALA) and its derivatives like the new
lipophilic agent methyl aminolevulinate (MAL). MAL-PDT is applied
as a cream under occlusion for 3 hours before illumination with
high intensity red light. For Europe, the European Medical
Evaluation Agency (EMEA) labelled MAL as indication for AK. The
clinical experience in AK patients receiving MAL-PDT shows complete
response rate of 70-78% after a single treatment session and 90%
after two treatment sessions one week apart. Negative effects of
PDT are local pain, risk of photosensitivity (mainly for ALA) and
time delay between application of cream and treatment. Photodynamic
therapy in comparison to cryotherapy shows significantly better
cosmetic results – (evaluation by patients and doctors) ([31] -
level of evidence 2b, [42] - level of evidence 2b,
[43, 44] - level of evidence 2b[17]). Advantages of PDT
include the selective absorption and treatment of sub-clinical
lesions and the flourescence of the photosensitiser can be
visualised using Wood’s light before the initiation of therapy
[45]. On the other hand, the costs of treatment are considerably
higher compared to cryotherapy.
Imiquimod
Imiquimod 5%, a member of a novel class of immune response
modifiers (IRMs), is a toll-like receptor (TLR) 7-agonist and
stimulates the immune response by induction, synthesis and release
of cytokines. These cytokines increase the cellular immunity.
Therefore it has an indirect antiviral and anti-tumoral potency
[46, 47]. Topically applied imiquimod causes a local skin reaction,
including erythema, itching, and burning, that is generally mild to
moderate in intensity – also fever can occur (especially in larger
treated areas and/or mucosal application). Apart from the
capability of imiquimod to ‘light-up’ sub-clinical AKs, imiquimod
is effective and safe in patients with AKs. Response rates show
complete remission in 84%; a recurrence rate of 10% within 1-year
follow up and 20% within 2-years follow up ([48] - level of
evidence 2b,[49] - level of evidence 2b). A randomised,
double-blind, placebo-controlled study in 436 patients with actinic
keratoses showed a complete resolution of all lesions in 45.1% (vs.
3.2% placebo) and a partial reduction of actinic keratoses in 59.1%
(vs. 11.8% placebo) after a treatment period of 16 weeks (twice per
week) [Lebwohl et al. 2004 - level of evidence 2b]. A label
for the indication of AK through the EMEA is in process. Imiquimod
is labelled for the indication of superficial basal cell carcinoma
in the USA, Australia and Europe.
Topical 5-fluorouracil
5-fluorouracil (5-FU) is a topical chemotherapeutic antimetabolite
that destroys clinical foci via interference with DNA and RNA by
blocking the methylation reaction of deoxyuridylic acid to
thymidylic acid. Hereby 5-FU interferes with the synthesis of DNA
and, to a lesser extent, inhibits the formation of RNA. 5-FU can be
used for the treatment of multiple lesions and is applied twice a
day (2-4 weeks). These effects may cause life-risk complications if
dihydropyrimidine-dehydrogenase-deficency exists [50]. Topical 5-FU
can results in severe dermatitis with wound infections, pruritus,
pain and ulceration with scarring and the application is of limited
help in the therapy of extensive AKs. A reduction of severe side
effects can be realised by using intermittent “pulse” 5-FU therapy
which is a less intensive way of employing 5-FU and may be of value
in patients unwilling to accept the erosions and discomfort that
accompany the traditional course of daily 5-FU applications ([51] -
level of evidence 3b). For localised disease, clearance
rates of approximately 50% and recurrence rates up to 55% have been
reported with 5-FU ([35, 52] - level of evidence 2c, [53] -
level of evidence 3b). Meanwhile, new formulations with
different concentrations and galenics of 5-FU are under clinical
investigations ([54] - level of evidence 3a, [53] - level
of evidence 3b, [55] - level of evidence 2c, [56]).
Retinoids
Retinaldehyde is a natural derivative of vitamin A; it has effects
similar to retinoic acid [57]. Besides counteracting the UV-induced
vitamin A deficiency of the epidermis, topical retinaldehyde may
have an antioxidant effect [58, 59] and decreases the number of
sunburn cells. A placebo-controlled randomised study documents that
systemic administered etretinate reduces AKs in 85% ([60] -
level of evidence 2b). Some publications show that the
epidemiological characteristics of AKs were not modified by the
application of retinaldehyde and that retinaldehyde has no
prophylactic effects on the development of AKs ([61] - level of
evidence 3a, [62] - level of evidence 3a). Side effects
of topically applied retinoids are increased sensitivity to
sunlight, erythema, erosions, pruritus and pain.
Retinoids can also be administered orally especially in patients
who develop large numbers of skin cancers [63]. Systemic therapy
can be considered for high risk patients - such as patients with
inherited disorders such as xeroderma pigmentosum (abnormal repair
of UV-induced DNA damage), nevoid basal cell carcinoma syndrome
(tumour suppressor gene abnormality) or in after organ-transplant
recipients with chronic immunosuppression ([64, 65] - level of
evidence 3a). The use of retinoids for the treatment of AKs is
currently an off-label use.
Diclofenac in hyaluronic acid gel
Within the last years antineoplastic properties of selective
inhibitors of cyclo-oxygenase 2 (COX-2 have increasingly been
investigated). These new agents inhibit prostaglandin E2 synthesis
(PGE2) which is known to suppress the production of
immune-regulatory lymphocytes, T-and B-cell proliferation and the
cytotoxic activity of natural killer cells. Furthermore activation
of COX-2 has implications for tumour angiogenesis through
up-regulation of vascular endothelial growth factor (VEGF), which
is a potent angiogenic factor required for tumor growth and
metastases [66]. Apart from its affinity to the inducible COX-2,
NSAIDs have been demonstrated to activate peroxisome
proliferator-activated-receptor-gamma (PPAR-gamma) which decreases
cancer cell proliferation. Topical diclofenac is applied in
hyaluronic acid (HA). Several randomised, double blind, HA gel
vehicle-controlled clinical studies have evaluated the efficacy of
topical diclofenac HA gel in patients with AK. The 30-day interval
between the end of treatment and the evaluation of efficacy was due
to earlier findings stating a significant advantage for diclofenac
HA gel over placebo, when efficacy was evaluated 4 weeks after the
end of treatment. The product significantly reduced lesions when
applied for 60 or 90 days bid. A double-blind, randomised,
placebo-controlled multicenter study showed responding rates of 79%
(verum group) versus 45% in the placebo group; a complete healing
was seen in 50% (verum group) versus 20% in the control group (p
< 0.001%) ([67] - level of evidence 2b]). Other
controlled studies showed similar effects ([68] - level of
evidence 2b, [69] - level of evidence 2b). Adverse
effects were skin related and mild to moderate in severity
(pruritus, erythema, dry skin, hyp- and paraesthesia). Systemic
bioavailability of diclofenac was demonstrated to be considerably
lower after topical application than after systemic administration
and the drug demonstrated a good safety profile.
Prevention
Prevention of AKs is an important part in AK-management [70, 71].
Education of patients (UV-protection, self-examination, and
detection of early lesions) is particularly important. AK is an
ongoing disease that requires frequent follow-up (half-yearly to
yearly) and long-term management.
Summary of recommendations
It has to be declared that the physician who cares about the
patient has always to keep in mind the inidividual needs of the
patient. The physician has to respect the individuality of the
patient and has to see the guideline as recommendation and
supporting device for therapeutical strategies and efforts.
Guideline development standard operating Procedure of EDF
(table 3)
( Table 3 )Appendix (table 4( Table 4 ))
Table 3 Guideline development standard operating
Procedure of EDF
|
Step
|
Responsible
|
Task
|
Months duration
|
|
1
|
EDF Guidelines Committee (EDF-GC)
|
Decision of topic of specific guideline
|
∅
|
|
2
|
EDF Guidelines Committee
|
Foundation of subcommittee for specific guidelines, nomination of
EDF members (50%)
|
at EDF Meeting
|
|
3
|
EDF Guidelines Committee
|
Ask EADV to send in 25% of members for the subcommittee
|
2
|
|
4
|
EDF Guidelines Subcommittee (EDF-GSubC)
|
Identify all existing guidelines for the specific guideline (active
process: literature survey plus contact to Dermatological
Societies)
|
1
|
|
5
|
EDF Guidelines Subcommittee
|
Select the guidelines with highest quality. Criteria for
selection:
|
1
|
|
1. Availability of strength of evidence
|
|
2. Availability of strength of recommendation
|
|
3. Evidence of mechanics of literature review
|
|
6
|
EDF Guidelines Subcommittee
|
Identification/nomination of additional 50% EDF members for the
EDF-GSubC from amongst the authors of the best guidelines
|
0.5
|
|
7
|
EDF Guidelines Subcommittee
|
Nomination of chairperson for EDF-GSubC from the GSubC members
|
0.5
|
|
8
|
Chairperson of Subcommittee
|
Consider involvement of other disciplines and patients´
organisations
|
1
|
|
9
|
EDF Guidelines Subcommittee
|
Meet
|
6
|
|
1. to decide the author of the first draft and to discuss the
present guidelines, their strengths and weaknesses
|
|
2. 6 months later to discuss the draft (consensus conference)
|
|
10
|
Chairperson
|
Circulate the guideline draft to national dermatological societies
for comments
|
2
|
|
11
|
Guidelines Subcommittee
|
Circulate final version for approval among members of the guideline
subcommittee
|
1
|
|
12
|
Chairperson of Subcommittee
|
Deliver final version for comments to
|
2
|
|
1. EDF guideline chairperson
|
|
2. EADV Board
|
|
3. UEMS
|
|
13
|
EDF Guidelines Committee
|
Review and comment guideline
|
1
|
|
14
|
EDF Guidelines Committee chairperson
|
Send guideline for official approval to UEMS (formal approval)
|
1
|
|
15
|
EDF secretary
|
Distribute guideline for in advance information to EDF members and
National Dermatological Societies
|
1
|
|
16
|
EDF
|
Publication
|
6
|
|
1. on EDF homepage
|
|
2. in European Journal of Dermatology and Journal of Deutsche
Dermatologische Gesellschaft
|
|
3. If publication in other national journals is requested by the
respective society, this will be encouraged by the EDF
|
Table 4
|
Level
|
Therapy/Prevention, Aetiology/Harm
|
Prognosis
|
Diagnosis
|
Differential diagnosis/symptom prevalence study
|
Economic and decision analyses
|
|
1a
|
SR (with homogeneity) of RCTs
|
SR (with homogeneity) of inception cohort studies; CDR validated in
different populations
|
SR (with homogeneity) of Level 1 diagnostic studies; CDR with 1b
studies from different clinical centres
|
SR (with homogeneity) of prospective cohort studies
|
SR (with homogeneity) of Level 1 economic studies
|
|
1b
|
Individual RCT (with narrow Confidence Interval)
|
Individual inception cohort study with ≥ 80% follow-up; CDR
validated in a single population
|
Validating cohort study with good reference standards; or CDR
tested within one clinical centre
|
Prospective cohort study with good follow-up
|
Analysis based on clinically sensible costs or alternatives;
systematic review(s) of the evidence; and including multi-way
sensitivity analyses
|
|
1c
|
All or none
|
All or none case-series
|
Absolute SpPins and SnNouts
|
All or none case-series
|
Absolute better-value or worse-value analyses
|
|
2a
|
SR (with homogeneity) of cohort studies
|
SR (with homogeneity) of either retrospective cohort studies or
untreated control groups in RCTs
|
SR (with homogeneity) of Level >2 diagnostic studies
|
SR (with homogeneity) of 2b and better studies
|
SR (with homogeneity) of Level >2 economic studies
|
|
2b
|
Individual cohort study (including low quality RCT; e.g., < 80%
follow-up)
|
Retrospective cohort study or follow-up of untreated control
patients in an RCT; Derivation of CDR or validated on split-sample
only
|
Exploratory cohort study with good reference standards; CDR after
derivation, or validated only on split-sample or databases
|
Retrospective cohort study, or poor follow-up
|
Analysis based on clinically sensible costs or alternatives;
limited review(s) of the evidence, or single studies; and including
multi-way sensitivity analyses
|
|
2c
|
“Outcomes” Research; Ecological studies
|
“Outcomes” Research
|
|
Ecological studies
|
Audit or outcomes research
|
|
3a
|
SR (with homogeneity) of case-control studies
|
|
SR (with homogeneity) of 3b and better studies
|
SR (with homogeneity) of 3b and better studies
|
SR (with homogeneity) of 3b and better studies
|
|
3b
|
Individual Case-Control Study
|
|
Non-consecutive study; or without consistently applied reference
standards
|
Non-consecutive cohort study, or very limited population
|
Analysis based on limited alternatives or costs, poor quality
estimates of data, but including sensitivity analyses incorporating
clinically sensible variations.
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4
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Case-series (and poor quality cohort and case-control studies)
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Case-series (and poor quality prognostic cohort studies)
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Case-control study, poor or non-independent reference standard
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Case-series or superseded reference standards
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Analysis with no sensitivity analysis
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5
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Expert opinion without explicit critical appraisal, or based on
physiology, bench research or “first principles”
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Expert opinion without explicit critical appraisal, or based on
physiology, bench research or “first principles”
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Expert opinion without explicit critical appraisal, or based on
physiology, bench research or “first principles”
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Expert opinion without explicit critical appraisal, or based on
physiology, bench research or “first principles”
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Expert opinion without explicit critical appraisal, or based on
economic theory or “first principles”
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