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Cochrane Database of Systematic Reviews Protocol - Intervention

Systemic steroids for acute gout

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of systemic steroids in the treatment of acute gout in comparison with other drugs (NSAIDs, colchicine), placebo or other therapies.

Background

Gout is a frequent form of arthritis, mostly of the first metatarsophalangeal joint. It occurs suddenly and in most patients it disappears completely within 5 to 14 days. The severe and painful inflammation is caused by deposition of monosodium urate crystals in the affected joint. Without definite evidence it is assumed that the etiology of urate crystal deposition is high blood levels of uric acid, caused by metabolic overproduction and/or renal under secretion (Bieber 2004). Uric acid is an end product of purine nucleotide catabolism, which is excreted largely by the kidneys. Gout affects at least 1% of adult men in Western countries (Terkeltaub 2003, Bieber 2004). The estimated incidence of gout in these countries is 0.6 to 2.1 per 1000 per year (Arromdee 2002, Van de Lisdonk 2003, Schlesinger 2004, Van der Linden 2004), with a prevalence of 3 to 7.5 per 1000 per year (Van de Lisdonk 2003, Schlesinger 2004, Van der Linden 2004).

In current practice, non‐steroidal anti‐inflammatory drugs (NSAIDs), colchicine, systemic and intra‐articular steroids are used in the treatment of acute gout. NSAIDs are widely accepted as the drugs of first choice. In the past decades, several studies have shown the effectiveness of NSAIDs in patients with acute gouty arthritis in reducing pain, swelling, disability, redness and temperature. (Sturge 1977, Maccagno 1991, Shrestha 1995, Schumacher 2002). Gastrointestinal complications are the most frequent adverse effects of NSAIDs. These adverse effects can emerge even within a short period of use. In Western European countries, 160 t6 2,000 deaths, and 2,000 to 10,000 admissions to hospital annually are related to NSAIDs (Hooper 2004, Moens 2004). Other less frequent side effects of NSAIDs are: allergic symptoms, headache, dizziness and sleepiness. Furthermore, decreased renal function in patients with chronic gout has been attributed to the use of NSAIDs (Perez‐Ruiz 2000). Finally, administration of NSAIDs may be problematic because most patients with gout are middle aged or older, and are often suffering from hypertension, cardiovascular morbidity, while (associated) renal defects or diseases are supposed to be frequent causes of gout (Abbott 1988, Conaghan 1994, Fam 1998b, Janssens 2003, Bieber 2004).

Colchicine has a longstanding history in the treatment of acute gout, even before NSAIDs were available. Despite its long tradition in the treatment of gout, we found only one placebo controlled trial with colchicine (Ahern 1987). All other data reported were based on reviews rather than on prospective studies (Schlesinger 2004). Colchicine has been considered as a first alternative when NSAIDs are contraindicated (Fam 1998a), but it is known to have a narrow therapeutic window. High dose schedules are advised until relief of pain is obtained or vomiting or diarrhoea occurs (Fam 1998a, Conaghan 1994, Morris 2003). The plasma half‐life of colchicine was found to be longer when renal function is impaired (Wise 1996). As noted before, a decreased renal function is often seen in patients with gout. Other infrequent, but serious, side effects are: bone marrow suppression, myopathy and neuropathy (Conaghan 1994).

Beneficial therapeutic effects of short‐term treatments with systemic corticosteroids in patients with acute gout has been shown in several original studies (Groff 1990, Alloway 1993, Siegel 1994, Werlen 1996). As they are the most potent anti‐inflammatory agents that are available, corticosteroids may exert their beneficial effect in acute gouty inflammation by directly suppressing the cells involved in the inflammatory process (Groff 1990). We could not find evidence‐based studies showing important adverse effects from systemic corticosteroids, provided that they are used during a short period (less than 2‐3 weeks). If used chronically (more than 3 to 6 months) adverse effects are of greater concern, i.e. osteoporosis with higher risks of bone fractures. Systemic use of corticosteroids has been considered as a safe first alternative to NSAIDs or colchicines to treat gout attacks, particularly in elderly people (Fam 1998b). The value of intra‐articular injection of a depot steroid for gout affecting one or two joints, have been described in several publications, in particular if the diagnosis needs to be confirmed by a joint tap (Schumacher 1996, Terkeltaub 2003, Schlesinger 2004). We were not able to find systematic reviews about short‐term treatment with systemic steroids in patients with acute gout. Existing reviews do not focus on treatment with systemic steroids but on on gout in general with subsections about different kinds of therapy (Groff 1990, Schumacher 1996, Fam 1998a, Wise 1996, Terkeltaub 2003, Schlesinger 2004). We propose a systematic review to evaluate all current evidence and safety for the therapeutic effect of systemic steroids in the treatment of acute gout.

Objectives

To assess the efficacy and safety of systemic steroids in the treatment of acute gout in comparison with other drugs (NSAIDs, colchicine), placebo or other therapies.

Methods

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials and controlled clinical trials will be included. We will include studies both published and unpublished studies without a language restriction.

Types of participants

Trials with patients with a diagnosis of acute gouty arthritis as demonstrated by the presence of crystals in joint fluid, will be included. Because of the expected limited number of trials adhering at this criterion, we will also include trials with patients diagnosed according to the criteria of the American College of Rheumatology (the ACR‐criteria) or on other clinical grounds. Studies with patients of any age will be included.

Types of interventions

Mono‐therapy with systemic steroids during at least 5 and at most 15 days compared with:
1. NSAIDs
2. Colchicine
3. Placebo
4. Other therapies
5. No therapy

Types of outcome measures

Primary outcomes:
1. Patient assessment of pain and/or disability
2. Investigators' assessment of clinical symptoms (swelling, erythema, tenderness).
3. Adverse events

Secondary outcomes:
4. Cost‐effectiveness

Search methods for identification of studies

ELECTRONIC SEARCHES
We will use the following (electronic) databases for the identification of trials:

* The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL)
* PUBMED (including MEDLINE and a number of additional journals) 1966 to 2005
* EMBASE (1974‐2005)
* Web of Science (1975‐2005),
* LILACS (www.bireme.br/bvs/I/ibd.htm) from 1986 to 2005
* Databases of ongoing trials (up to 2005):
Current Controlled Trials (http://www.controlled‐trials.com ‐ with links to other databases of ongoing trials); UK National Research Register (http://www.update‐oftware.com/National/nrr‐frame.html); USA ‐ Center Watch Clinical Trials Listing Service (http://www.CenterWatch.com/); USA ‐ National Institutes of Health
(http://clinicalstudies.info.nih.gov/).

The described search strategy (see below) will be used for PUBMED. For use with EMBASE and Current Contents this strategy will be slightly adapted because these databases have different interfaces. The necessary changes in the search string will be done in such a way that the search becomes more sensitive (i.e. yields a higher number of 'hits').

HAND SEARCHING
Additional studies will be identified by searching the reference lists of relevant trials and reviews.

OTHER SOURCES
Authors of relevant identified studies and other experts, including the offices of national Arthritis Societies, associated with the European League Against Rheumatism (EULAR) or the International League Against Rheumatism (ILAR), will be contacted in order to obtain additional references, unpublished trials, ongoing trials, and missing data not reported in original trials. Additional key words of relevance may be identified during any of the electronic of other searches. If this is the case, electronic strategies will be modified to incorporate these terms.

SEARCH STRATEGY
We will perform a search model combining procedures, in search of clinical trials, gout, and steroids. In the search of clinical trials we will use a sensitive and valid procedure (Robinson 2002); in the search strategy for gout and steroids we developed a strategy using keywords (Mesh headings) and text words. We extensively tested our procedures by running the searches, and subsequently checking whether known articles on the topic of gout or corticosteroids were missing. In case of missing articles we adjusted the model and repeated the procedure until all known articles were included.
The following strategy for electronic searches will be used. These searches can be cut and paste into PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi):

mh: exploded medical subject heading (Medline medical index term); mh:noexp: non‐exploded medical subject heading (Medline medical index term); tw = text word; pt = publication type.
The asterisk (*) stands for any character(s)

#1 Gout
"gout" [mh] OR gout* [tw] OR "Hyperuricemia"[mh] OR toph* [tw] OR arthritis uric* [tw] OR artritis uric* [tw] OR uric acid dis* [tw]

#2 Corticosteroids
"Glucocorticoids"[mh] OR "Adrenal Cortex Hormones"[mh] OR "Steroids"[mh] OR glucocortic* [tw] OR adrenal Cortex Horm* [tw] OR prednison* [tw] OR prednisol* [tw] OR cortison* [tw] OR hydrocort* [tw] OR methylprednis* [tw] OR triamcinol* [tw] OR dexamethas* [tw] OR betamethas* [tw] OR beclomethas* [tw] OR paramethas* [tw] OR dexametas* [tw] OR betametas* [tw] OR beclometas* [tw] OR parametas* [tw]

#3 Controlled trials (Robinson 2002)
(Randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (clinical trial [tw]) OR ((singl*[tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (latin square [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow‐up studies [mh] OR prospective studies [mh] OR cross‐over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh])

Whole search
#1 AND #2 AND #3

Data collection and analysis

STUDY SELECTION
To determine studies for further assessment, two independent observers (HJ and PL) will review the titles, abstract sections and key words of every record retrieved. Articles will be selected if the information from title, abstract section, or key words indicates that the study (1) includes patients with crystal proven gout or patients with a gout diagnosis based on the ACR‐criteria, or with a diagnosis on other clinical grounds; (2) compares systemic steroids treatment with placebo or other interventions; (3) assesses one ore more of the outcome measures; (4) uses random allocation to the comparison groups. If there is any doubt regarding the information of title, abstract section, or key words the full article will be retrieved for clarification. Because of the expected limited number of trials, methodological quality will not be a limitation for study inclusion. When disagreement exists about including a study a third observer (EvdL) will asked to make a definite decision. Inter‐observer agreement for study selection will be measured using the kappa statistic (Cohen 1960).

QUALITY ASSESSMENT OF SELECTED STUDIES
Two reviewers will assess the quality of each retrieved trial independently, using the following criteria:
1. Selection bias: A) method of randomisation; the randomisation procedure will be scored adequate when the resulting sequences are unpredictable (i.e. computer generated schemes, tables of random numbers, coin tossing). B) allocation concealment; allocation concealment will be scored adequate when participating patients and investigators cannot foresee assignment (i.e. by central randomisation remote from trial site, sequentially numbered and sealed radio‐opaque envelopes).
2. Performance bias: methods of (double) blinding (if applicable): blinding will be considered adequate when the interventions are similar in size, colour and shape or when a double dummy method was applied.
3. Attrition bias: A) description of withdrawals and dropouts; handling of drop outs will be considered adequate when studies give a complete description of all patients failing to participate until the end of the trial and when the data are analysed on intention‐to‐treat basis. B) number of drop outs: overall drop out rate <15% will be considered adequate; selective drop out: a difference in drop out rate between the groups <10% will be considered adequate.
4. Detection bias: this item is particularly relevant when researchers assess outcomes of redness and swelling in treated patients. So assessors have to be blind for the intervention.

In addition to these criteria, studies will be broadly subdivided into the following three categories as recommended in the Cochrane Handbook (Higgins 2005):
A ‐ All quality criteria met (1. adequate randomisation and allocation concealment, 2. adequate blinding, 3. adequate ITT analysis and/or both drop‐out rate less than 15% and selective drop‐out less than 10%): low risk of bias.
B ‐ One or more quality criteria only partially met (1. adequate randomisation or adequate allocation concealment, 2. mentioning of blinding but exact method unclear, 3.
inadequate/unclear ITT analysis but drop‐out less than 15% or selective drop‐out less than 10%): moderate risk of bias.
C ‐ One or more quality criteria not met (1. inadequate randomisation and allocation concealment, 2. inadequate or no blinding, 3. inadequate ITT and drop‐out rate equal to or greater than 15% and selective drop‐out equal to or greater than 10%): high risk of bias.
We will explore the influence of individual quality criteria in a sensitivity analysis (see under 'data analysis'). In cases of disagreement, the rest of the group will be consulted and a judgment will be made based on consensus.

DATA EXTRACTION
Two reviewers, using a standard data extraction form, will extract data concerning characteristics of the selected studies independently. This form will at least include the following items:
1. General aspects: published/unpublished; title, authors, source, contact address; language of publication; year of publication; duplicated publication; sponsoring.
2. Trial characteristics: design and setting; randomisation (and method); allocation concealment (and method); blinding (patients, people administering treatment, outcome assessors) and check of blinding.
3. Interventions details: placebo and/or comparison interventions (does, route, timing); co‐medication or other accompanying treatment (dose, route, timing).
4. Patients aspects: sampling (random/convenience); exclusion criteria; total number and number in comparison groups; age, sex, and other baseline characteristics; diagnostic criteria; only new or all cases; similarity of groups at baseline (including any co‐morbidity); assessment of compliance; withdrawals/losses to follow‐up (reasons/description).
5. Quality of outcome measures (pain/disability/clinical improvement): methods: continuous scales (e.g. visual analogical scales), dichotomous outcomes (e.g. presence/absence of pain), point scales (e.g. "none", "mild", "moderate", "severe", "extreme"), validated questionnaires, or others reported methods; length of follow‐up; quality of reporting the outcomes.

DATA ANALYSIS
Data will be summarised statistically, if they are available and sufficiently similar, and if they have enough quality. We expect dichotomous, ordinal and continuous data.
Dichotomous data will be expressed as relative risks (RR) and Peto odds ratio (Peto OR) will be used when incidence rates are small. We will calculate the risk difference (RD) and we will convert the RD into number needed to treat (NNT) or the number needed to harm (NNH). Continuous data will be expressed as weighted mean differences (WMD) when outcomes are measured in a similar way. In all other cases, standardised mean differences (SMD) will be used.
Overall results will be calculated based on the random effects model. Heterogeneity will be tested for using the Z‐score and the Chi‐square statistic with significance being set at p<0.10. Quantification of the effect of heterogeneity will be assessed by means of 'I squared', ranging from 0‐100% including its 95% confidence interval (Higgins 2002). 'I squared' demonstrates the percentage of total variation across studies due to heterogeneity and will be used to judge the consistency of evidence. Possible sources of heterogeneity will be assessed by sensitivity analyses and subgroup as described below. Publication bias will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.
The analyses will be done with the most recent version of MetaView in Review Manager (Cochrane Collaboration, Oxford, U.K.).

SENSITIVITY AND SUBGROUP ANALYSES
We will perform sensitivity analyses taking into account the influence of the following factors on effect size:
1. Repeating the analysis excluding unpublished studies (if there were any)
2. Comparing studies with and without (or with unknown) quality characteristics: adequate randomisation, adequate allocation concealment, adequate method of blinding, adequate ITT analyses, adequate blinding outcome‐assessment (if applicable), adequate method of blinding of analyses. Further, comparing studies with an overall drop‐out rate more than or equal to 15% and less than 15%, difference of drop‐out rates less than 10% and more than or equal to 10% between the main treatment groups. In addition, the overall score for quality based on the Cochrane criteria will be used so that studies with score A and B compared to studies with C.
3. Repeating the analysis excluding verge large or long studies to evaluate how much they influence the results.
4. Repeating the analysis excluding trials using the following filters: diagnostic criteria; language of publication; source of funding (industry versus other); country.

Subgroup analyses will be performed to explore effect size differences. Variables that we will include are:
1. Age
2. Gender
3. The way of administration (oral, rectal, intramuscularly)
4. Type of steroid
5. Dose (low, medium, high ‐ based on data)
6. Duration of intervention
7. Diagnosis criteria (crystal proven, according ACR, other)
8. Race
9. Blood level uric acid.

The robustness of the results will be further explored by repeating the analysis using different measures of effect size (relative risk, risk difference) and different statistic models (fixed and random effects models).

GRADING OF THE EVIDENCE
We will use the grading system described in the 2004 book Evidence‐based Rheumatology (Tugwell 2004) and recommended by the Musculoskeletal Group:
Platinum: A published systematic review that has at least two individual controlled trials each satisfying the following :
·Sample sizes of at least 50 per group ‐ if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome.
·Blinding of patients and assessors for outcomes.
·Handling of withdrawals >80% follow up (imputations based on methods such as Last Observation Carried Forward (LOCF) are acceptable).
·Concealment of treatment allocation.

Gold: At least one randomised clinical trial meeting all of the following criteria for the major outcome(s) as reported:
·Sample sizes of at least 50 per group ‐ if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome.
·Blinding of patients and assessors for outcomes.
·Handling of withdrawals > 80% follow up (imputations based on methods such as LOCF are acceptable).
·Concealment of treatment allocation.

Silver: A systematic review or randomised trial that does not meet the above criteria. Silver ranking would also include evidence from at least one study of non‐randomised cohorts that did and did not receive the therapy, or evidence from at least one high quality case‐control study. A randomised trial with a 'head‐to‐head' comparison of agents would be considered silver level ranking unless a reference were provided to a comparison of one of the agents to placebo showing at least a 20% relative difference.

Bronze: The bronze ranking is given to evidence if at least one high quality case series without controls (including simple before/after studies in which patients act as their own control) or if the conclusion is derived from expert opinion based on clinical experience without reference to any of the foregoing (for example, argument from physiology, bench research or first principles).

CLINICAL RELEVANCE TABLES
Clinical relevance tables will be compiled under additional tables to improve the readability of the review. For dichotomous outcomes, the number needed to treat will be calculated from the control group event rate and the relative risk using the Visual Rx NNT calculator (Cates 2003). Continuous outcome tables will also be presented under additional tables. Absolute benefit will be calculated as the improvement in the intervention group minus the improvement in the control group, in the original units. Relative difference in the change from baseline will be calculated as the absolute benefit divided by the baseline mean of the control group.