Description of the condition
Urticaria is a common skin disease triggered by a variety of underlying and potential causes, characterised by the development of wheals (hives), angioedema (swelling of deeper layers of the skin), or both (Zuberbier 2013). The skin lesions, which have a well-defined raised edge, may be round, annular, or serpiginous (having a wavy edge). They are erythematous (reddish) plaques with a central pallor that are variable in size. Urticarial lesions are extremely itchy.
In chronic urticaria, the symptoms persist for at least six weeks by definition and last for three to five years on average. It is quite common for the course of chronic urticaria to last for more than 20 years (Wedi 2008). The first step in the diagnosis of chronic urticaria is based on a thorough history. A physical examination including a provocation test is needed for the second step in diagnosis (Zuberbier 2013). The risk factors cannot be identified in 75% of those with chronic urticaria, as there may be a variety of triggers, such as physical causes; infections; drugs; foods; or vasculitic diseases (Kulthanan 2007; Vonakis 2008), and because of the uncertainty of its cause, it is referred to as chronic idiopathic urticaria.
It is estimated that the prevalence of chronic idiopathic urticaria is approximately 1% of the general population in the United States at any given time, and that figure is considered to be similar in other countries (Gaig 2004; Greaves 2000).
Chronic idiopathic urticaria is a disabling disease having a negative impact on the quality of life as a result of the intense itch (pruritus), which is often worse at night, therefore, causing sleep disturbance and secondary psychosocial problems, such as anxiety and consequent disruption to school and work (Wedi 2008).
Description of the intervention
Spontaneous remission tends to occur at any time and is not associated with urticarial severity. An effective treatment is needed for chronic idiopathic urticaria because of its profound impact on the quality of life. The first-line treatment recommended for urticaria is non-sedating H1 antihistamine (Zuberbier 2009). However, some people with this chronic form of urticaria do not respond to antihistamines. Alternative treatments need to be considered (Zuberbier 2006), and several forms of treatments have been used for chronic idiopathic urticaria, including corticosteroids, ciclosporin, and antileukotrienes (Grattan 2007; Zuberbier 2009). These are outlined below.
- Corticosteroids are frequently used in acute urticaria and acute exacerbations of the chronic form of the disease (Grattan 2007; Zuberbier 2009). Corticosteroids may reduce disease duration (Zuberbier 1996) and improve urticarial vasculitis (Grattan 2007), but they should not be used as a long-term medication for urticaria (Grattan 2007).
- Ciclosporin is used for people with severe chronic idiopathic urticaria refractory to any dose of antihistamine (Grattan 2007; Zuberbier 2009). Ciclosporin plays a role in the treatment of urticaria through the direct effect on mast cell mediator release (Stellato 1992) and inhibiting basophil histamine release (Zuberbier 2009).
- Omalizumab, a humanised anti-IgE (immunoglobulin E) monoclonal antibody, has been used in the treatment of severe persistent allergic disease (Maurer 2011). The mechanism by which omalizumab has been used for chronic idiopathic urticaria involves the reduction of the level of IgE autoantibodies and down-regulation of IgE receptor density on cutaneous mast cells (Maurer 2011; Zuberbier 2009).
- Phototherapy is beneficial to treatment-resistant patients with chronic idiopathic urticaria by reducing the numbers of mast cells in the upper dermis (Engin 2008; Zuberbier 2009). It has been used as a combination treatment with antihistamines for chronic idiopathic urticaria and symptomatic dermographism (Borzova 2008; Engin 2008).
- Alternative treatments need to be considered as an add-on to high-dose antihistamine therapy, but it needs clearly stating that corticosteroids should only be used as a short-term intervention.
Why it is important to do this review
Chronic idiopathic urticaria is a complex disease that significantly affects a person's quality of life, although it is not life-threatening. The standard treatment used for its management are H1 antihistamines. Higher doses of H1 antihistamines or H1 antihistamines in combination with H2 antihistamines may be applied in some cases. A Cochrane systematic review (Fedorowicz 2012) has been completed on histamine H2-receptor antagonists for urticaria, and a Cochrane review on H1 antihistamines for chronic urticaria is in preparation (Stanway 2006). Besides antihistamines, there is no standardised evidence base for alternative treatments, although guidelines have been published on the interventions for chronic idiopathic urticaria excluding antihistamines (Zuberbier 2013). Therefore, reviews of randomised controlled trials aiming to evaluate the use of interventions for chronic idiopathic urticaria excluding antihistamines are necessary.
This review will determine the current state of evidence of the non-antihistamine therapies for chronic idiopathic urticaria and will aim to add to the current evidence base to guide clinical decisions on the rational use of such therapies.
To assess the effects of interventions for chronic idiopathic urticaria excluding antihistamines.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials on non-antihistamine interventions for chronic idiopathic urticaria.
Types of participants
Adults and children with clinically diagnosed chronic idiopathic urticaria (with symptoms lasting for at least six weeks).
Types of interventions
We will include all interventions excluding antihistamines. The interventions will include the following:
- ciclosporin A;
- oral corticosteroids;
- intravenous immunoglobulins (IVIG);
- other non-antihistamine pharmacological interventions;
- phototherapy; and
- Complementary & Alternative Medicine (CAM), including traditional Chinese medicines and acupuncture.
We will compare all of the listed interventions either alone or in combination with placebo, another active intervention, and no interventions.
Types of outcome measures
- Change in urticaria activity from baseline in the immediate period (the first 24 hours), the short-term (up to six weeks), and long-term (longer than six weeks) since the intervention was given in the study. The Urticaria Activity Score (UAS) is a frequently used scoring system that measures the intensity of pruritus and number of wheals (Mlynek 2008). We will also accept other measures used by trialists.
- Serious adverse events that require withdrawal of the treatment.
- The proportion of participants with 50% or greater improvement in quality of life (QoL) measurements whilst taking the intervention in the short-term (up to six weeks) and long-term (longer than six weeks). Two QoL questionnaires have been developed specifically for chronic spontaneous urticaria: the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) (Baiardini 2005) and the Angioedema QoL Questionnaire (AE-QoL) (Weller 2012). We will also accept other measures used by trialists.
- Time to resolution of urticaria.
- Chronic urticaria-associated discomfort and sleep disturbance (Mlynek 2009).
- Adverse events not requiring withdrawal of the treatment.
Timing of outcome assessment
The measurement timings of all of the listed outcomes are in the immediate period (the first 24 hours), the short-term (up to six weeks), and long-term (longer than six weeks and up to six months) from when the intervention was given in the study.
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);
- AMED via OVID (Allied and Complementary Medicine Database, from 1985);
- China National Knowledge Infrastructure (CNKI) (from 1979); and
- Airiti Library (from 1991).
We have devised a draft search strategy for randomised controlled trials (RCTs) for MEDLINE (OVID), which is displayed in Appendix 1. We will use this as the basis for search strategies for the other databases listed.
We will search the following trials registers.
- The metaRegister of Controlled Trials (www.controlled-trials.com).
- The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
- The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
- The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).
- The EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/).
Searching other resources
References from included studies
We will scan references of included studies on treatment of chronic idiopathic urticaria for relevant RCTs.
We will also contact specialists in the field, authors of the included trials, and pharmaceutical manufacturers for any relevant unpublished data.
We will not perform a separate search for adverse effects of the target intervention. However, we will examine data on adverse effects from the included studies we identify.
Data collection and analysis
We plan to include at least one 'Summary of findings' table in our review. In this, we will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of findings' tables.
Selection of studies
Two authors (JingWen Deng and Jingjie Yu) will independently assess each retrieved report for eligibility in order to select the relevant studies, and they will resolve any disagreements through discussion with a third author (Xinfeng Guo). We will contact trialists for additional information if necessary.
Data extraction and management
Two authors (JingWen Deng and Zehui He) will independently extract the data using a prespecified data extraction form that has been piloted before being applied to all studies. We will resolve discrepancies in the results by discussion. Information extracted will include methods, participants, interventions, and outcomes.
Assessment of risk of bias in included studies
We will assess the quality of included studies according to the following components, as advised in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011):
(a) the method of random sequence generation;
(b) the method of allocation concealment;
(c) the methods of blinding of participants, researchers, and outcome assessors;
(d) the number of the participants lost to follow up in each arm and the reasons for losses;
(e) whether all participants are analysed according to their originally randomised group, i.e. intention-to-treat (ITT) analysis;
(f) whether there are other problems that can put the study at high risk of bias, like baseline imbalance, deviation from the study protocol, dropouts or withdrawals from treatment, or insensitive outcome measurement tools; and
(g) selective reporting of outcomes.
We plan to contact the trialists to seek clarification where necessary.
Measures of treatment effect
We will calculate risk ratios (RR) and 95% confidence intervals (CI) for dichotomous variables. We will calculate mean differences (MD) and 95% CIs for continuous outcomes using similar scales. We will calculate standardised mean differences (SMD) and 95% CIs for continuous outcomes using different scales.
Dealing with missing data
We will contact the original researchers of studies less than 10 years old for missing data. When the missing data are not available, we will initially assume those data are missing at random. If the missing data are caused by participants' dropout, we will conduct an intention-to-treat analysis. For dichotomous outcomes, we will regard participants with missing outcome data as treatment failures and include them in the analyses. For continuous outcomes, we will carry forward the last recorded value for participants with missing outcome data if the data are available. Where high levels of missing data are seen within the analyses, we will conduct sensitivity analyses to assess the robustness of the results from the approach described above by comparing the results with those that exclude the missing data from the analyses (i.e. available case analysis).
Assessment of heterogeneity
We will use the I² statistic to assess the heterogeneity of the pooled intervention estimates of the included trials. If the I² statistic is 50% or higher, we will regard this as moderate to substantial levels of heterogeneity and pool results. If there is severe heterogeneity (I² statistic > 85%), we will not conduct a meta-analysis, and we will explore the causes of heterogeneity among results of studies by subgroup analysis. We will interpret the results with caution.
Assessment of reporting biases
We will use a funnel plot to assess reporting biases when there are at least 10 studies reporting a primary outcome for an intervention.
For studies on a similar type of intervention, we will conduct meta-analysis using a fixed-effect model to calculate a pooled intervention effect estimate across trials when the I² statistic is less than 50% with reasonable clinical homogeneity. If the I² statistic is 50% to 80%, we will apply a random-effects model. If there is severe heterogeneity (I² statistic > 80%), we will not conduct a meta-analysis. Where it is inappropriate or impossible to perform a meta-analysis, we will summarise the data narratively for each trial.
Subgroup analysis and investigation of heterogeneity
We will base subgroup analysis on disease severity, dosage, and participant characteristics. 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 using subgroup analyses.
We will conduct sensitivity analyses on primary outcome measures to assess the effects after excluding trials of lower methodological quality and after excluding the missing data.
Sincere thanks to the Cochrane Skin Group for their guidance and assistance with this project. Thanks to Elizabeth Doney for designing the search strategy. The review team would like to thank Chunxia He and Wanhua Zhou (consumers).
The Cochrane Skin Group editorial base wishes to thank Ching-Chi Chi who was initially the Cochrane Dermatology Editor for this protocol and then agreed to join the author team in response to our request; Matthew Grainge and Philippa Middleton who were the Statistical and Methods Editors, respectively; the clinical referee, Torsten Zuberbier; and the consumer referee, Jo Clayton.
Appendix 1. MEDLINE (OVID) draft search strategy
3. chronic urticaria.ti,ab.
4. ordinary urticaria.ti,ab.
5. idiopathic urticaria.ti,ab.
7. randomized controlled trial.pt.
8. controlled clinical trial.pt.
11. clinical trials as topic.sh.
14. 7 or 8 or 9 or 10 or 11 or 12 or 13
15. exp animals/ not humans.sh.
16. 14 not 15
17. 6 and 16
Contributions of authors
Chuanjian Lu was the contact person with the editorial base.
JingWen Deng co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
Zehui He and Xin-Feng Guo worked on the methods sections.
JingWen Deng, Jingjie Yu, and Yuhong Yan drafted the clinical sections of the background and responded to the clinical comments of the referees.
Zehui He responded to the methodology and statistics comments of the referees.
Charlie Changli Xue and Ching-Chi Chi contributed to writing the protocol.
Anthony Lin Zhang contributed to the methods section and provided critical comments on the manuscript.
Weifeng Zeng was the consumer co-author and checked the protocol for readability and clarity. She also ensured that the outcomes are relevant to consumers.
Chuanjian Lu is the guarantor of the final review.
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.
Declarations of interest
Sources of support
- No sources of support supplied
- The National Institute for Health Research (NIHR), UK.The NIHR, UK, is the largest single funder of the Cochrane Skin Group.