This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the efficacy and the safety of systemic treatment with methotrexate for moderate to severe plaque psoriasis, psoriatic erythroderma, and generalised pustular psoriasis.
Description of the condition
Psoriasis is a common skin condition characterised by persistent localised scaly pink patches on the elbows, knees, and scalp. It is a chronic disease that progresses slowly over a long period of time, with symptoms that frequently recur. The disease affects approximately 1% to 2% of the general population in the UK and USA (Fairhurst 2005). Both genetic inheritance and environmental factors, such as infection, trauma, and medication, contribute to the development of psoriasis (Menter 2009; Wolff 2007). The disease may begin at any age, but it is uncommon in children under 10 years of age. It occurs more usually between 15 and 30 years of age (Wolff 2007). It is a disease that has a negative impact on a person's quality of life (Carretero 2010), where even a mild degree of involvement may have an important impact on self-esteem (Menter 2009).
Psoriasis is a common inflammatory, proliferative immune-mediated skin condition. It is characterised by increased cell growth (hyperproliferation) and abnormal differentiation of epidermal keratinocytes, which are the cells that make up the outermost layer of the skin and produce keratin. There is also abnormal activity of the body's immune system with T lymphocytes (a type of white blood cell in the immune system) infiltrating the dermal layer, which is the layer of skin between the epidermal and subcutaneous tissues. These all contribute to vascular changes to the skin (Krueger 2005; Wolff 2007).
The most common clinical presentation consists of scaling, thickened skin, and erythematous (reddened) plaques (patches of abnormal skin more than 1 cm in diameter, which feel different from the rest of the skin) that may affect any area of the body surface (Menter 2009). The clinical presentation of psoriasis is variable with several subtypes, such as plaque psoriasis, psoriatic erythroderma (an inflammatory skin disease with redness and scaling that affects nearly the entire skin surface), generalised pustular psoriasis (which appears as pus-filled spots), nail psoriasis, palmoplantar psoriasis, and psoriatic arthritis (a form of joint disorder that involves inflammation of one or more joints) (Carretero 2010). Approximately 80% of people with psoriasis have mild to moderate psoriasis, and 20% have more severe disease (Menter 2009).
The treatment of psoriasis can be a challenge because of its multifactorial nature and the fact that each person's needs may require a unique approach.
Description of the intervention
Methotrexate is used to treat moderate to severe plaque psoriasis, psoriatic erythroderma, generalised pustular psoriasis, nail psoriasis, palmoplantar psoriasis, and psoriatic arthritis. Its use for the treatment of psoriasis was approved by the United States' Food and Drug Administration in 1972 (Carretero 2010).
Administration of methotrexate can be oral, intravenous, intramuscular, or subcutaneous. Most physicians prescribe a single weekly oral dose; this usually starts at a low dose to reduce adverse effects, and then it is gradually increased to achieve efficacy (Menter 2009). Occasionally, methotrexate is prescribed as a parenteral solution, i.e. either intramuscularly when there is gastrointestinal intolerance or subcutaneously (where it can be administered at home).
Methotrexate is a synthetic chemical analogue of folic acid, and because of this similar structure, it can inhibit metabolic processes that use folic acid (Carretero 2010). Because of this, most physicians recommend that all those receiving methotrexate should take a daily folate supplement (Menter 2009).
There are many contraindications to the use of methotrexate for those who are pregnant, nursing, and for both men and women planning to have children. This is because it may cause the unborn baby to have abnormalities, or it may induce an abortion. It should not be prescribed for people with chronic liver disease, significant anaemia, leucopenia (decrease in the number of white blood cells), or thrombocytopenia (relative decrease of platelets in the blood) (Barker 2011). Other contraindications are alcohol abuse, acute peptic ulcer (ulcer of an area of the gastrointestinal tract), active infections, severe respiratory failure, immunodeficiency (where the immune system's ability to fight infectious disease does not function properly), and those who are unlikely to take the medication as prescribed (Bolognia 2008; Carretero 2010).
The main side-effect of methotrexate is hepatotoxicity (chemical-driven liver damage) in those receiving long-term treatment. Additionally, methotrexate may cause pulmonary toxicity and myelosuppression (decreased production of blood cells), and hence also immunosuppression (Barker 2011).
How the intervention might work
Methotrexate is a drug that is used world-wide for the treatment of all types of psoriasis and other inflammatory diseases. Methotrexate has a triple mode of action: It is anti-inflammatory; it reduces cell proliferation; and it is immunosuppressant (it reduces the activation or efficacy of the immune system) (Carretero 2010).
Methotrexate is administered orally or parenterally (i.e. intramuscular or intravenous), and it is not difficult to use. The oral mode of administration achieves reliable drug levels.
Why it is important to do this review
Methotrexate is a drug that is currently used in the treatment of moderate to severe plaque psoriasis, psoriatic erythroderma, generalised pustular psoriasis, nail psoriasis, palmoplantar psoriasis, and psoriatic arthritis, but there is no systematic review assessing its efficacy and safety.
To assess the efficacy and the safety of systemic treatment with methotrexate for moderate to severe plaque psoriasis, psoriatic erythroderma, and generalised pustular psoriasis.
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) examining the efficacy and safety of systemic methotrexate in people with psoriasis.
Types of participants
Participants with psoriasis (moderate to severe plaque psoriasis, psoriatic erythroderma, generalised pustular psoriasis) who have been diagnosed by a physician, with no restrictions for age, sex, or ethnicity. For the diagnosis, we will accept clinical presentation, skin biopsy, or both.
We will exclude studies if they focus exclusively on guttate psoriasis, palmoplantar pustular psoriasis, or psoriatic arthritis. These are covered in other Cochrane reviews (Chalmers 2000; Chalmers 2006; Jones 2000).
Types of interventions
We will consider trials if the following are compared to placebo or other active systemic or topical therapies:
methotrexate at any dose;
different routes of administration of methotrexate:
oral or parenteral (i.e. intramuscular or intravenous);
different duration of therapy and any follow-up time.
Types of outcome measures
Improvement in psoriasis severity, which is assessed by grading systems such as PASI score (Psoriasis Area and Severity Index), the extent of Body Surface Area (BSA) involved, or a global improvement scale (Bolognia 2008; Schmitt J 2005).
Improvement in participant quality of life score as measured by validated psoriasis-specific, skin disease-specific, or generic quality of life scales such as the Psoriasis Disability Index (PDI), Skindex-16, Skindex-29, and EQ-5D.
Incidence and severity of adverse effects (e.g. development of hepatic fibrosis).
Duration of treatment response as measured by the baseline score (PASI score) during continued treatment or following discontinuation of treatment.
Reduction of severity as measured by self-assessment or during the course of the intervention, using a validated instrument such as PDI, PQOL-12, Skindex-16, Skindex-29, SF36, DLQI, and EQ-5D.
Time to next flare.
Timing of outcomes
We shall regard short-term outcomes as those with a duration of follow-up to 6 months and long-term outcomes with a duration of follow-up to 12 months.
Dose of MTX
We will consider maintenance doses of 25 mg/week or higher as high doses, doses of 7.5 mg/week as low doses, and values in-between as standard doses.
Dose of folic acid
We will consider a high dose of folic acid as 5 mg/day or higher, a low dose as 1 mg/day, and values in-between as standard doses.
Route of administration
We will consider oral, intramuscular, and subcutaneous as routes of administration.
Search methods for identification of studies
We aim to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).
We will search the following databases for relevant trials:
the Cochrane Skin Group Specialised Register;
the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;
MEDLINE via OVID (from 1946);
EMBASE via OVID (from 1974);
LILACS (Latin American and Caribbean Health Science Information database, from 1982).
We devised a draft search strategy for randomised controlled trials (RCTs) for MEDLINE (OVID), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.
We will search the following trials registers.
We will look at our included and excluded RCTs for common adverse effects. We will also do a separate search of MEDLINE and EMBASE (via OVID) for non-randomised studies (case controls and cohort) on adverse effects using the Skin Group's standard adverse effects search strategy and the intervention terms. We will qualitatively summarise any findings in the discussion section of our review.
Searching other resources
We will check the bibliographies of included studies for further references to relevant trials.
We will contact specialists in the field, authors of the included trials, and pharmaceutical manufacturers for any possible unpublished data.
Data collection and analysis
Selection of studies
After merging the search results and removing duplicate records, we will examine titles and abstracts to select the relevant reports. Two authors (CAPS and KVK) will independently screen the trials identified by the literature search. We will retrieve and examine the full text of selected studies for compliance with eligibility criteria. We will document the reason for exclusion of individual trials. We will consult a third author (RR) in the case of any disagreements (at this or at any other stage as listed below).
Data extraction and management
Two authors (CAPS and KVK) will extract data independently and collect data on a paper data extraction form. We will resolve discrepancies in the results by discussion. We will collect the following information.
1. Study features
publication details (e.g. year, country, authors)
population data (e.g. age, psoriasis baseline aspects such as type, comorbidities, severity, duration, history concerning treatments and responses, wash-out period)
details of interventions (e.g. doses, regimen, route of administration, scheme, comedication such as folic acid, increasing or decreasing dose)
number of participants randomised into each treatment group
the number of participants in each group who were cured or failed treatment
the numbers of participants lost to follow up
the duration of follow-up
Assessment of risk of bias in included studies
In order to assess the risk of bias, we will independently assess the quality of the studies included in the review according to the criteria described by Higgins (Higgins 2011).
We will assess the following domains and rate them as at low, unclear, or high risk of bias:
random sequence generation;
adequate concealment of allocation;
blinding of participants, personnel, and outcome assessment;
incomplete outcome data;
selective outcome reporting; and
other potential threats to validity.
We will report these assessments for each individual study in the 'Risk of bias' tables located in the 'Characteristics of included studies' section.
We plan to contact the study author(s) to seek clarification in case of uncertainty over data.
Measures of treatment effect
We will calculate risk ratios (RR) and 95% confidence intervals (CIs) for dichotomous variables. We will calculate the mean difference (MD) and 95% CIs for continuous outcomes that have used similar scales. We will calculate the standardised mean difference (SMD) and 95% CI for continuous outcomes where different scales have been used. In the event that study authors do not make the necessary information available, we will insert any data from primary studies that are not parametric (e.g. effects reported as medians, quartiles, etc) or without sufficient statistical information (e.g. standard deviations, numbers of participants, etc) into an 'Additional table'. For time-to-event outcome (time to next flare), we will also use hazard ratios to measure the treatment effect.
Unit of analysis issues
We will deem the individual participant as our unit of analysis (unit to be randomised for interventions to be compared), i.e. the number of observations in the analysis should match the number of individuals randomised.
If we find cross-over studies and consider them adequate for inclusion in the meta-analysis, we will include the data using the results of paired analyses (Elbourne 2002).
We will evaluate studies with multiple treatment groups relevant to the review by combining the groups of the study to create a single pair-wise comparison.
Dealing with missing data
For missing or unavailable data, we will contact the study authors for additional information. In case of non-response, irrespective of the type of data, we will report dropout rates in the 'Characteristics of included studies' tables of the review, and we will use intention-to-treat analysis.
Assessment of heterogeneity
We will qualify inconsistency among the pooled estimates using the I² statistic (where I² = ((Q - df)/Q) x 100% where Q is the Chi² statistic, and df represents the degree of freedom). This illustrates the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2011).
We will interpret the thresholds for the I² statistic as follows:
0% to 25% = low heterogeneity;
25% to 75% = moderate heterogeneity; and
more than 75% = substantial heterogeneity (Higgins 2003).
Assessment of reporting biases
We will assess reporting biases or small study effects by drawing a funnel plot (trial effect versus trial size) if we include a sufficient number of studies (more than 10) in the review.
If we do not identify substantial heterogeneity, we will compute pooled estimates of the treatment effect for each outcome under a fixed-effect model. Otherwise, if we identify substantial heterogeneity, we will perform a random-effects analysis.
Subgroup analysis and investigation of heterogeneity
If possible, we intend to perform subgroup analyses to consider the following:
age (children and adults);
severity of the disease: moderate or severe;
type of disease: plaque psoriasis, psoriatic erythroderma, or generalised pustular psoriasis;
different doses and schemes: We will consider maintenance doses of 25 mg/week or higher as high doses, doses of 7.5 mg/week as low doses, and values in-between as standard doses; we will consider a high dose of folic acid as 5 mg/day or higher, a low dose as 1 mg/day, and values in-between as standard doses.
types of intervention: intramuscular, oral, or subcutaneous; and
duration of the treatment.
If we find substantial heterogeneity, and there are sufficient data, we will investigate the possible causes by further exploring the impact of the condition of the individuals and interventions (i.e. participant characteristics, degree and duration of the intervention, adjuvant drugs) using subgroup analyses. We will test for subgroup differences using interaction tests.
If there are an adequate number of studies, we will perform sensitivity analyses based on separation of studies according to allocation concealment quality (high, low, or unclear) and blinding of outcome assessment (high, low, or unclear).
We will carry out sensitivity analysis by excluding trials of low and moderate methodological quality as defined by the 'Risk of bias' table. We will present these results and compare them with the overall findings.
The authors would like to thank the Brazilian Cochrane Centre Study Group for their methodological support.
The Cochrane Skin Group editorial base wishes to thank Luigi Naldi who was the Key Editor for this protocol; Jo Leonardi-Bee and Philippa Middleton who were the Statistical and Methods Editors, respectively; the clinical referees, Phyllis Spuls and Stef Menting; and the consumer referee, Jack Tweed.
Appendix 1. MEDLINE (OVID) search strategy
1. exp Psoriasis/ or psoria$.mp.
2. palmoplantar$ pustulosis.mp.
3. pustulosis palmaris et plantaris.mp.
4. (pustulosis and palms and soles).mp.
5. 1 or 2 or 3 or 4
6. exp Methotrexate/
11. 6 or 7 or 8 or 9 or 10
12. randomized controlled trial.pt.
13. controlled clinical trial.pt.
16. clinical trials as topic.sh.
19. 12 or 13 or 14 or 15 or 16 or 17 or 18
20. exp animals/ not humans.sh.
21. 19 not 20
22. 5 and 11 and 21
Contributions of authors
CAPS was the contact person with the editorial base.
CAPS co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
CAPS, TM, and RR worked on the methods sections.
CAPS drafted the clinical sections of the background and responded to the clinical comments of the referees.
CAPS and KVK responded to the methodology and statistics comments of the referees.
CAPS contributed to writing the protocol.
MRL was the consumer co-author and checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers.
CAPS is the guarantor of the final review.