Intervention Protocol

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Oral fumaric acid esters for psoriasis

  1. Ausama Atwan1,
  2. Rachel Abbott2,
  3. Mark J Kelly3,
  4. Timothy Pickles3,
  5. Andrea Bauer4,
  6. Chris Taylor5,
  7. Vincent Piguet1,
  8. John R Ingram1,*

Editorial Group: Cochrane Skin Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD010497


How to Cite

Atwan A, Abbott R, Kelly MJ, Pickles T, Bauer A, Taylor C, Piguet V, Ingram JR. Oral fumaric acid esters for psoriasis (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD010497. DOI: 10.1002/14651858.CD010497.

Author Information

  1. 1

    Cardiff University, Department of Dermatology & Wound Healing, Cardiff Institute of Infection & Immunity, Cardiff, UK

  2. 2

    University Hospital of Wales, Welsh Institute of Dermatology, Cardiff, UK

  3. 3

    Cardiff University, South East Wales Trials Unit, Institute of Translation, Innovation, Methodology and Engagement, Cardiff, Wales, UK

  4. 4

    University Hospital Carl Gustav Carus, Technical University, Department of Dermatology, Dresden, Germany

  5. 5

    c/o Cochrane Skin Group, The University of Nottingham, Nottingham, UK

*John R Ingram, Department of Dermatology & Wound Healing, Cardiff Institute of Infection & Immunity, Cardiff University, 3rd Floor, Glamorgan House, Heath Park, Cardiff, CF14 4XN, UK. ingramjr@cardiff.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

A glossary of technical terms is available in  Table 1.

 

Description of the condition

Psoriasis is a chronic inflammatory skin disease, which can be divided into a number of subtypes. The most common subtype is chronic plaque psoriasis, which presents as well-defined erythematous scaly plaques typically on the elbows, knees, and scalp. Other subtypes include flexural psoriasis, in which erythematous plaques are located in the skin creases; guttate psoriasis, in which there are multiple small plaques, particularly on the trunk; generalised pustular psoriasis, involving multiple skin pustules; and erythrodermic psoriasis covering nearly all the skin surface (Lebwohl 2003). Diagnosis is based on typical clinical features; a skin biopsy can also be helpful if there is diagnostic uncertainty. Psoriatic nail changes, including onycholysis and nail pitting, occur in about 40% of people with psoriasis (Augustin 2010).

 

Epidemiology

Psoriasis occurs world wide and has a higher prevalence in countries further from the equator (Parisi 2012). In the United Kingdom (UK), it affects about 2% of the population (Smith 2006). The incidence of psoriasis has two peaks: in the fourth decade of life, and a second peak occurs in the sixth and seventh decades (Icen 2009). It probably affects men and women about equally (Griffiths 2007).

The cause of psoriasis is thought to be a combination of genetic and environmental risk factors (Smith 2006). A family history of psoriasis increases the risk of developing the condition, but in studies of twins, psoriasis in one identical twin does not always predict psoriasis in the other (Duffy 1993). Environmental exposures can precipitate psoriasis in some cases, such as streptococcal throat infections leading to guttate psoriasis (Telfer 1992), and medications, including beta-blockers, may trigger chronic plaque psoriasis (Basavaraj 2010). Skin trauma (e.g. due to surgery) can precipitate psoriasis at the surgical site, an observation known as the Koebner phenomenon. Possible links with smoking, alcohol consumption, obesity, and stress remain more controversial, because these may be secondary consequences rather than primary causes (Huerta 2007).

Psoriasis is associated with psoriatic arthritis, an inflammatory arthritis that may involve the axial skeleton or more peripheral joints. Nail involvement has been shown to increase the risk of psoriatic arthritis (Griffiths 2007). Population studies suggest that severe psoriasis may be an independent cardiovascular risk factor (Mehta 2010).

 

Pathogenesis

Psoriasis is thought to be mediated by cells of the immune system. This is supported by resolution of psoriasis after bone marrow transplants from another donor (Eedy 1990), the benefit obtained by immunosuppressive treatments, and genetic studies. PSORS1, located on chromosome 6, is the disease susceptibility gene locus most strongly linked with psoriasis (Nestle 2009). It contains genes encoding the major histocompatibility complex.

Cells of both the innate and adaptive immune systems are involved. In particular, T helper 1 and T helper 17 cells are important components of the immune cell cascade that results in psoriasis (Nestle 2009). These cells secrete cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-17, which cause skin inflammation. Several biologic treatments, such as anti-TNF-α therapies, have been developed to specifically target elements of the inflammatory cascade (Smith 2009).

However, pathogenic pathways in psoriasis are not limited to the immune system. Keratinocytes, which are non-immune cells that form the skin barrier, also play a role by secreting chemokines that attract immune cells to the area (Nestle 2009). In addition, tissue samples have demonstrated that new blood vessel formation is a characteristic finding within psoriatic plaques, so angiogenic mediators, such as vascular endothelial growth factor, represent another potential psoriasis pathway (Heidenreich 2009).

However, understanding of pathogenesis remains incomplete.

 

Impact

Psoriasis is a stigmatising condition, and it can have a major impact on quality of life, equivalent to conditions such as cancer, heart disease, and diabetes (Rapp 1999). Occupational, psychological, and social elements of quality of life can all be greatly affected because of the impact of psoriasis on appearance and function (Kimball 2005). Personal life choices may be profoundly restricted by the condition (Warren 2011). Psoriasis can be itchy and painful, and application of topical therapies is time consuming and may involve mess and odour. Systemic oral therapies may have adverse effects and usually require blood-test monitoring. The impact of psoriasis extends beyond individuals as it may also detrimentally affect other members of the family (Eghlileb 2007).

 

Description of the intervention

Oral fumaric acid esters (FAE) contain a mixture of dimethylfumarate (DMF), thought to be the active component, and three salts of ethyl hydrogen fumarate (Mrowietz 1999). Fumaderm® initial, containing 30 mg of dimethylfumarate per tablet, and Fumaderm®, containing 120 mg of dimethylfumarate per tablet, are commercially available. Fumaderm® has been licensed for psoriasis in Germany since 1994. At treatment initiation, gradual dose increments are recommended to improve gastrointestinal tolerance, from one tablet daily of Fumaderm® initial to a maximum of six tablets daily of Fumaderm® (Pathirana 2009). Using the recommended dosing increments, treatment benefit is usually seen after about six to eight weeks (Pathirana 2009). Most clinical data regarding efficacy relates to chronic plaque psoriasis.

 

Adverse effects

Adverse effects of FAE occur in about two thirds of treated patients, particularly during the period of dose escalation (Pathirana 2009). These are usually mild, but can lead to treatment discontinuation (Mrowietz 1999). The most frequent adverse effects are gastrointestinal symptoms, including diarrhoea, increased stool frequency, nausea, and abdominal pain, as well as facial flushing. A decrease in the circulating lymphocyte count is seen in the majority of patients, but this does not usually require treatment to be discontinued, and transient increases in the eosinophil count may occur (Hoefnagel 2003). Pregnancy and breastfeeding are considered absolute contraindications to fumaric acid esters, because of a lack of safety data in this group. Severe gastrointestinal or kidney disease are also contraindications to the use of fumaric acid esters (Pathirana 2009).

 

How the intervention might work

The exact mechanisms of action of FAE are not yet fully understood, but there is increasing evidence of anti-inflammatory effects via a number of pathways. Within psoriatic plaques, dimethylfumarate reduces the levels of several inflammatory T cell subsets (Bovenschen 2010). This may be due to decreased recruitment of inflammatory cells from the blood stream (Rubant 2008). Fumarates also induce type II dendritic cells, which have an anti-inflammatory effect mediated by the cytokine interleukin-10 (Ghoreschi 2011). In addition, FAE have been shown to inhibit the formation of new blood vessels, a process that is involved in the formation of psoriatic plaques (García-Caballero 2011; Meissner 2011).

 

Why it is important to do this review

Current licensed oral systemic therapies, namely methotrexate, acitretin, and ciclosporin, are not effective in all psoriasis patients and may cause adverse effects that require discontinuation of treatment. The next licensed step in treatment is expensive biologic treatment, such as anti-TNF-α therapy. Fumaric acid esters are a cheaper alternative systemic therapy that are licensed in Germany, and the 2011 update of German S3 guidelines recommended FAE as a first-line systemic agent for moderate to severe psoriasis (Nast 2012). However, FAE are unlicensed in many other countries, which limits their clinical use and has restricted production of guidelines to assist patients and clinicians. For example, FAE are used to treat many individuals with psoriasis in the UK, but no guidance exists from the National Institute for Health and Clinical Excellence (NICE) or the British Association of Dermatologists. This means that there is no standardisation of prescribing fumaric acid esters, and many dermatologists choose not to consider their use for psoriasis because of the lack of guidance. As a result, inequalities exist in psoriasis care due to patient location. This review is intended to assist in decision-making between patients and clinicians regarding choice of systemic therapy for psoriasis.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the efficacy and safety of fumaric acid esters for psoriasis.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

We will include randomised controlled trials, including cross-over trials.

 

Types of participants

We shall include individuals of either sex and any age and ethnicity, with a clinical diagnosis of psoriasis made by a medical practitioner. We will include all subtypes of psoriasis.

 

Types of interventions

We shall include all randomised controlled trials that compare fumaric acid esters, with or without another systemic or topical active treatment, with placebo or another active treatment:

  1. fumaric acid esters versus oral placebo;
  2. fumaric acid esters versus active treatment;
  3. fumaric acid esters in combination with another active treatment versus placebo; or
  4. fumaric acid esters in combination with another active treatment versus active treatment.

We will consider trials of FAE other than the formulation licensed in Germany, Fumaderm®, if the dimethylfumarate content is specified, including dimethylfumarate monotherapy.

 

Types of outcome measures

 

Primary outcomes

  1. Psoriasis Area and Severity Index (PASI) score.
  2. The proportion of participants who discontinued treatment due to adverse effects that are common but sufficiently serious that the drug has had to be stopped, such as severe diarrhoea, infections, or cutaneous malignancy.

 

Secondary outcomes

  1. Quality of life score at follow-up measured with a validated scale.
  2. The proportion of participants attaining PASI 50, 75, and 90, defined as a 50%, 75%, or 90% reduction in PASI score relative to the baseline PASI score immediately prior to treatment initiation.
  3. The proportion of participants experiencing any adverse effects of treatment, i.e. all nuisance side-effects that are common, but do not mean that the drug is stopped.
  4. The proportion of participants experiencing serious adverse effects of treatment, defined as resulting in death, hospital admission, or increased duration of hospital stay.

Timing of outcome measures

We anticipate that the outcome measures may be of two types: those in which the treatment phase has finished and those in which the treatment phase is ongoing. We will include studies of any duration, but we will undertake an a priori subgroup analysis to investigate the influence of duration of treatment. We will divide studies into short-term treatment duration of less than 12 weeks, medium-term duration from 12 weeks to less than 6 months, and long-term duration of 6 months or greater.

Economic data

If the included studies provide any relevant data, we will incorporate health resource usage data in the discussion section of the review to place the clinical findings in an economic context.

 

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).

 

Electronic searches

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); and
  • LILACS (Latin American and Caribbean Health Science Information database, from 1982).

We have 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.

 

Searching other resources

 

Trials registers

We will search the following trials registers:

 

Handsearching

In order to identify other potential RCTs for inclusion, AA and RA will handsearch the abstracts of proceedings from the following major dermatology conferences that are not already recorded in the Cochrane Skin Group Specialised Register:

  • American Academy of Dermatology (2008/2009);
  • British Association of Dermatologists (2008/2009/2010);
  • European Academy of Dermatology and Venereology (EADV) (from 2006 to the present);
  • European Society for Dermatological Research (ESDR) (2005/2006/2007/2008/2009);
  • International Investigative Dermatology (from 2003 to the present); and
  • Society for Investigative Dermatology (SID) (2007/2008/2009).

 

Grey literature

We will check the reference lists of included and excluded studies for further references to relevant trials, and we will correspond with authors where necessary to determine if a study meets the criteria for inclusion.

 

Correspondence

We will contact by e-mail the corresponding authors of included and excluded FAE clinical trials to check for unpublished RCTs. We will correspond with authors where necessary to determine if a study meets the criteria for inclusion.

 

Adverse effects

From the included studies we identify, we will examine data on adverse effects of the interventions. However, we will not perform a separate search for rare or delayed adverse effects.

 

Translations

We will impose no language restrictions on this review, and we will translate those trials that are not published in English.

 

Data collection and analysis

 

Selection of studies

Two authors (AA and RA) will independently compare the titles and abstracts of the studies retrieved by the searches with the inclusion criteria. They will examine the full texts of studies that potentially meet the criteria, as well as the studies whose abstracts do not provide sufficient information. A third author (JI) will resolve any disagreements in terms of final study selection. We will record the reasons for exclusion of studies in the 'Characteristics of excluded studies' tables.

 

Data extraction and management

Two authors (AA and RA) will independently extract data using a data extraction form based on the 'Checklist of items to consider in data collection or data extraction' found in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). A third author (JI) will resolve any disagreements. Two authors (AA and RA) will pilot the data collection form prior to use. We will enter the information collected in the 'Characteristics of included studies' tables.

 

Assessment of risk of bias in included studies

Two authors (AA and RA) will independently assess the methodological quality of included studies using the The Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011). The risk of bias will be graded as 'low', 'high', or 'unclear' for each of the following domains:

(a) random sequence generation;
(b) allocation concealment;
(c) blinding of participants, personnel, and outcome assessment;
(d) incomplete outcome data;
(e) selective outcome reporting (we will check trial databases to ensure that reported outcomes match to those prospectively listed); and
(f) other sources of bias.

 

Measures of treatment effect

We will express dichotomous outcome measures as risk ratios, with 95% confidence intervals (CIs). We will express continuous outcome measures as mean differences, with 95% CIs. We will analyse ordinal data from short outcome scales using the methods for dichotomous data, by combining relevant adjacent categories to form a dichotomy. We will treat longer outcome scales as continuous data.

 

Unit of analysis issues

We will permit the first phase of cross-over trials and pool the results with those from equivalent parallel-group RCTs. For cluster randomised trials, we will deflate the sample size using the design effect reported (Higgins 2011).

 

Dealing with missing data

Whenever possible, we will make contact with the original trial investigators to request any relevant unreported data. If this is unsuccessful, we will attempt to impute standard deviations for a small proportion of the included studies. We will explore the impact of missing data through sensitivity analyses. For missing dichotomous outcome data, we will conduct two sensitivity analyses in which we assume all missing data to be either events or non-events.  

 

Assessment of heterogeneity

We will assess statistical heterogeneity using the I² statistic. If the value of the I² statistic exceeds 75%, we will not perform a meta-analysis because of considerable heterogeneity, and we will take a narrative approach (O'Rourke 1989). An I² statistic of between 40% and 75% may represent substantial heterogeneity (Higgins 2011), and we will explore the potential causes where possible for the primary outcome measures.

 

Assessment of reporting biases

We will perform funnel plots and Egger's test for publication bias (Egger 1997) if 10 or more studies have contributed data.

 

Data synthesis

For dichotomous outcomes, we will pool risk ratios. For continuous outcomes, we will combine either standardised or unstandardised mean differences, depending on whether different scales have been used and whether change scores are to be combined with follow-up scores. If available, we will use follow-up scores rather than change from baseline, as recommended by The Cochrane Collaboration (Higgins 2011).

We will report pooled measures of effect with 95% confidence intervals and use a fixed-effect model, because we expect reasonable similarity across the included studies that involve the same disease and similar treatments and study populations. In the unlikely event that we need to adopt a random-effects model study during the analysis due to study heterogeneity, we will highlight this in the completed review, with detailed justification.

 

Subgroup analysis and investigation of heterogeneity

If we identify sufficient studies, we will perform subgroup analyses on the following variables:

  • treatment duration (short, medium, or long, defined as less than 12 weeks, 12 weeks to less than 6 months, or at least 6 months, respectively); and
  • types of intervention and comparison (fumaric acid esters versus placebo, fumaric acid esters versus active treatment, etc).

 

Sensitivity analysis

We will perform sensitivity analysis for studies at higher risk of bias, determined by allocation concealment and blinding of outcome assessment. We will conduct two sensitivity analyses in which all missing data are assumed to be either events or non-events.  

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The Cochrane Skin Group editorial base wishes to thank Esther J van Zuuren, who was the Key Editor for this protocol; Jo Leonardi-Bee and Philippa Middleton, who were the Statistical and Methods Editors, respectively; and the clinical and consumer referees, who wish to remain anonymous.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. MEDLINE (OVID) draft search strategy

1. exp Psoriasis/ or psoria$.mp.
2. exp Fumarates/
3. (fumar$ and esters).mp.
4. dimethylfumarate.mp.
5. fae.ti,ab.
6. dmf.ti,ab.
7. fumarate$1.ti,ab.
8. or/2-7
9. randomized controlled trial.pt.
10. controlled clinical trial.pt.
11. randomized.ab.
12. placebo.ab.
13. clinical trials as topic.sh.
14. randomly.ab.
15. trial.ti.
16. 9 or 10 or 11 or 12 or 13 or 14 or 15
17. exp animals/ not humans.sh.
18. 16 not 17
19. 1 and 8 and 18

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

JRI was the contact person with the editorial base.
JRI co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
RA, MJK, TP, AA, and JRI worked on the methods sections.
JRI and AA drafted the clinical sections of the background, and JRI responded to the clinical comments of the referees.
MJK and TP responded to the methodology and statistics comments of the referees.
AA, RA, JRI, AB, MJK, TP, CT, and VP contributed to writing the protocol.
CT was the consumer co-author and checked the protocol for readability and clarity. She also ensured that the outcomes are relevant to consumers.
JRI is the guarantor of the final review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

John Ingram's department has received unrestricted educational grants from Abbott, Janssen, MSD, Pfizer, and Galderma. His department benefits financially from The Dermatology Life Quality Index, via Professor Andrew Finlay, the joint copyright owner.

Vincent Piguet has received consulting fees from Abbott and Pfizer, and his department has received unrestricted educational grants from Abbott, Janssen, MSD, Pfizer, and Galderma. His department benefits financially from The Dermatology Life Quality Index, via Professor Andrew Finlay, the joint copyright owner.

The clinical referee, who wishes to remain anonymous, declared the following: "scientific support from Actelion, Biogen, and Pfizer; member of advisory boards Abbott, Pfizer, MSD, and Leo; speaker for Abbott, Pfizer, MSD, Leo, and Janssen".

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • No sources of support supplied

 

External sources

  • Psoriasis and Psoriatic Arthritis Alliance (PAPAA), UK.
    Grant award

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
Augustin 2010
Basavaraj 2010
Bovenschen 2010
  • Bovenschen HJ, Langewouters AM, van de Kerkhof PC. Dimethylfumarate for psoriasis: Pronounced effects on lesional T-cell subsets, epidermal proliferation and differentiation, but not on natural killer T cells in immunohistochemical study. American Journal of Clinical Dermatology 2010;11(5):343-50.
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    Direct Link:
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Rubant 2008
  • Rubant SA, Ludwig RJ, Diehl S, Hardt K, Kaufmann R, Pfeilschifter JM, et al. Dimethylfumarate reduces leukocyte rolling in vivo through modulation of adhesion molecule expression. Journal of Investigative Dermatology 2008;128:326-31.
Smith 2006
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Telfer 1992
  • Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Archives of Dermatology 1992;128(1):39-42. [MEDLINE: 1739285]
Warren 2011