On which evidence can we rely when prescribing off-label methotrexate in dermatological practice? - a systematic review with GRADE approach.

If an authorized drug is prescribed for a use that is not described in the Summary of Product Characteristics, this is defined as 'off-label use.' Methotrexate is often used off-label for dermatological indications. Off-label use is permitted if physicians can justify the treatment based on scientific evidence available to them. Our objective here was therefore to summarize the evidence for the effectiveness, efficacy, and safety of the dermatological off-label use of methotrexate in a systematic review. We searched MEDLINE, EMBASE, and CENTRAL for studies for evidence on the effectiveness, efficacy, and safety of the off-label use of methotrexate in dermatological indications up to November 2019. We used the GRADE system to rate the quality of the evidence. The search retrieved 34,583 hits of which 3566 were selected after the title and abstract screening. After the full-text screening, 143 studies were included, which involved 3688 patients in total. We found low-quality evidence for the effectiveness, efficacy, and safety of the off-label use of methotrexate in 31 dermatological diseases. To optimize the quality of evidence to support off-label use, we need high-quality studies in which well-characterized patients are treated with standardized treatments regimens using well-validated outcomes relevant to patients and physicians.

Prospective comparison of three guideline development methods for treatment of actinic keratosis.

OBJECTIVE: To compare three methods of guideline development, to see whether using alternative evidence-based methods resulted in variation of recommendations for treating actinic keratosis. METHODS: Method 1 followed a standard multiple session evidence-based approach with a working group. In method 2 recommendations were formulated by a working group during a 2-day conference. Method 3 used one epidemiologist to summarise the evidence and one dermatologist to make clinical recommendations afterwards. Graded recommendations and levels of evidence were compared per therapy across three draft guidelines. The primary outcome was the extent of accordance or discordance. Secondary outcomes were total costs and time period necessary to make a draft guideline. RESULTS: Therapeutic recommendations and levels of evidence differed in some occasions. However, intraclass correlations between levels of evidence were significant (method 1 vs 2: p = 0.003; method 1 vs 3: p < 0.001). Regarding recommendation variation method 1 and method 2 correlated significant at 0.755 (p = 0.001). Method 1 versus 3 and method 2 versus 3 also showed significant, but lower, correlation coefficients (respectively, 0.493 (p = 0.026) and 0.673 (p = 0.007)). Method 3 was the cheapest and quickest (24,770 euro and 4 months) and method 1 was the most expensive and slowest method (€48,100 euro and 14 months). CONCLUSIONS: The value of a guideline using alternative evidence-based methods seems to at least equal that of a guideline composed in multiple sessions, that is, for topics with a monodisciplinary character and a relatively small number of conducted trials. In addition, the presented alternatives were more time- and cost-efficient.

Off-label use of azathioprine in dermatology: a systematic review.

OBJECTIVE: To summarize evidence regarding the effectiveness, efficacy, and safety of off-label azathioprine use in dermatology. DATA SOURCES: We searched the MEDLINE (1950-2009), EMBASE (1980-2009), and CENTRAL (1996-2009) databases on October 9, 2009. The main search terms were azathioprine and its synonyms. No restrictions were imposed regarding publication date. Only articles in English, French, German, or Dutch were included. STUDY SELECTION: Randomized controlled trials, cohorts, and case series concerning the use of azathioprine in an off-label dermatologic setting were independently assessed for eligibility by 2 coauthors. The search retrieved 3870 articles, and 148 articles were selected for detailed review. DATA EXTRACTION: Forty-three articles matching the inclusion and exclusion criteria were reviewed for methodologic quality by 2 reviewers independently, including an evaluation of components associated with biased estimates of treatment effect. DATA SYNTHESIS: High-quality evidence (level A) was found for a moderate therapeutic effect in severe atopic dermatitis. Evidence of moderate quality (level B) was found for efficacy in parthenium dermatitis (an airborne plant allergen contact dermatitis), bullous pemphigoid, chronic actinic dermatitis, and leprosy type 1 reaction. Furthermore, favorable therapeutic effects existed for erythema multiforme, lichen planus, and pityriasis rubra pilaris, although the quality of evidence was low (level C). CONCLUSIONS: A strong clinical recommendation was given for azathioprine in atopic dermatitis. Conclusions regarding safety in an off-label setting could not be reached because of scarce and incomplete data (level C evidence). Long-term registries and prospective studies could add to the existing evidence and provide legal support for off-label drug use in dermatology.