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Intervention Protocol

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Interventions for reducing inflammation in familial Mediterranean fever

  1. Bin Wu1,
  2. Ting Xu1,
  3. Youping Li2,*,
  4. Xi Yin1

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 6 JAN 2014

Assessed as up-to-date: 18 DEC 2013

DOI: 10.1002/14651858.CD010893


How to Cite

Wu B, Xu T, Li Y, Yin X. Interventions for reducing inflammation in familial Mediterranean fever (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD010893. DOI: 10.1002/14651858.CD010893.

Author Information

  1. 1

    West China Hospital, Sichuan University, Department of Pharmacy, Chengdu, Sichuan, China

  2. 2

    West China Hospital, Sichuan University, Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, Chengdu, Sichuan, China

*Youping Li, Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. yzmylab@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 6 JAN 2014

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This is not the most recent version of the article. View current version (20 MAR 2015)

 

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
 

Description of the condition

Familial Mediterranean fever (FMF) is an autosomal recessive, hereditary auto-inflammatory disease (Online Mendelian Inheritance in Man (OMIM) ID: 249100). The primary characteristic of FMF is recurrent fever and serositis, which results in pain in the abdomen, chest, joints and muscles etc. This condition mainly affects ethnic groups living in the Mediterranean region, such as Jews, Armenians, Turks and Arabs, with a high prevalence of 1 in 200 to 1 in 1000 people affected (Shohat 2011; Soriano 2012). Regarding the rest of world, in Italy, Spain, Greece and Japan FMF is also not considered to be a rare disease (Konstantopoulos 2003; La Regina 2003; Migita 2012). Most patients with FMF (approximately 90 per cent) are diagnosed before the age of 20 years (Koné-Paut 2011).

Familial Mediterranean fever occurs as a result of mutations in the MEditerranean FeVer (MEFV gene). This is the only gene currently known to be associated with FMF and is located on chromosome 16 (Centola 2000). The MEFV gene is comprised of 10 exons encoding for a protein called pyrin (by the International FMF Consortium) (The International FMF Consortium 1997) or marenostrin (by the French FMF Consortium) (French FMF Consortium 1997). Pyrin consists of 781 amino acids, expressed in neutrophils, eosinophils, monocytes, dendritic cells and fibroblasts, and plays a key role in the regulation of inflammation and apoptosis (Chae 2009; Mansfield 2001). Pyrin contains a pyrin domain (PYD), two B-boxes, a coiled-coil domain (BBCC) and a SPRY domain (Papin 2007). The role of pyrin in the regulation of inflammation is still ambiguous. The PYD, shared with more than 20 other proteins (such as the NALP proteins), belongs to the death domain (DD) superfamily, which includes the PYD, death domain (DD), death effector domains (DED), and caspase recruitment domains (CARD). The DD superfamily is the interaction mediator which leads to apoptosis, inflammation and the innate immunity signalling pathway (Park 2012). Through homotypic PYRIN-PYRIN interaction, pyrin can interact with the adaptor protein, apoptosis-associated Speck-like protein with a CARD (ASC). This ASC (with an N-terminal PYD and a C-terminal CARD) is known as the inflammasome, which oligomerizes and mediates the proteolytic activation of caspase-1, inducing secretion of the potent pro inflammatory cytokine interleukin 1β (IL-1β) (Chae 2008). The interleukin-1 (IL-1) family, a group of 11 cytokines, plays a central role in the regulation of immune and inflammatory responses. In addition to PYD, the Pyrin SPRY domain interacts with NALP, caspase-1 and pro-interleukin-1b (proIL-1b) (Papin 2007). That means, an ineffective pyrin does not inhibit inflammation normally, resulting in inflammatory episodes. Pyrin can also interact with tubulin and colocalizes with microtubules (Mansfield 2001), suggesting a rationale for colchicine treatment.

There are mainly two phenotypes in FMF. Type 1 is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis and rarely pericarditis and meningitis (Shohat 2011). These symptoms and severity vary from one patient to another. The typical clinical manifestations of FMF type 1 usually last from 12 to 72 hours and include the following typical attacks (Shohat 2011; Soriano 2012):

  • recurrent fever, characterized by a temperature ranging from 38 ℃ to 40 ℃;
  • abdominal attacks, featuring abdominal pain (usually the entire abdomen is involved);
  • arthritic attacks, frequently featuring as monoarthritis localized in the large joints of the leg (hip, knee, ankle);
  • chest attacks, including pleuritis and pericarditis;
  • pre-attack symptoms, occurring 12 to 24 hours before any FMF attacks, usually including discomfort, abnormal taste sensation, dizziness, increased appetite, irritability and so on (Lidar 2006).

The most severe complication of FMF is AA amyloidosis leading to renal failure. Type 2 FMF is characterized by amyloidosis as the first clinical manifestation of the disease, in otherwise asymptomatic individuals (Livneh 2006). However, the existence of this phenotype is still controversial. Melikoğlu failed to prove the existence of type 2 FMF in their prospective designed study, even in siblings with significant proteinuria (Melikoğlu 2000). Furthermore, the common MEFV mutations are not significantly different between patients who present with the typical phenotype and those have clinical type 2 disease (Balci 2002).

 

Description of the intervention

During the FMF attack period, it is reported that febrile and inflammatory episodes are usually treated with non-steroidal anti-inflammatory drugs (NSAIDs) (Shohat 2011; Soriano 2012).

Colchicine is an anti-inflammatory drug and the most widely-chosen treatment option for preventing inflammatory attacks and the deposition of amyloid (Shohat 2011). It is an alkaloid which can be extracted from two plants of the lily family: Colchicum autumnale and Gloriosa superba and has been used for centuries in acute gout arthritis, but its anti-inflammatory efficacy has been demonstrated in other diseases as well. Colchicine was reported as an effective drug for preventing FMF attacks in the early 1970s (Goldfinger 1972). To prevent FMF attacks, it is mainly given orally, usually 1 mg to 2 mg per day in adults and 0.5 mg to 1 mg per day according to age and weight in children (Shohat 2011). After oral administration, colchicine is absorbed in the jejunum and ileum with a zero-order rate process, with a half-life of about four hours. Colchicine is mainly metabolised by the cytochrome P450 system in the liver and predominantly eliminated by biliary excretion with enterohepatic circulation (Cerquaglia 2005; Terkeltaub 2009).

For those FMF patients who are colchicine-resistant or colchicine-intolerant, a number of other drugs for treating FMF have been studied in clinical trials such as: anakinra (100 mg per day or every other day as a subcutaneous injection) (Ozen 2011); rilonacept (2.2 mg/kg (maximum, 160 mg) as a weekly, subcutaneous injection) (Hashkes 2012); etanercept (25 mg twice a week as a subcutaneous injection) (Bilgen 2011); infliximab (4 mg/kg to 5 mg/kg at zero, two and six weeks and then every eight weeks by infusion) (Özçakar 2012); thalidomide (100 mg per day, orally) (Seyahi 2006); and interferon-alpha (IFN-α) (3 million international units (IU) per attack by subcutaneous injection) (Tweezer-Zaks 2008).

 

How the intervention might work

Colchicine produces its anti-inflammatory activity through different pharmacologic effects (Ben-Chetrit 2006; Cerquaglia 2005; Cronstein 2006) such as:

  • preventing activation of neutrophils by binding β-tubulin to make β-tubulin-colchicine complexes, then inhibiting the assembly of microtubules and mitotic spindle formation;
  • inhibiting the synthesis of tumor necrosis factor alpha (TNF-α) and down-regulating the surface expression of TNF-α receptor;
  • inhibiting leukotriene B4 synthesis;
  • blocking cyclooxygenase-2 (COX-2) activity;
  • inhibiting tyrosine phosphorylation and superoxide anion production;
  • inhibiting arachidonate release and 5-lipoxygenase;
  • suppressing delayed hypersensitivity reactions, histamine, insulin and parathormone release.

Anakinra and rilonacept are IL-1 inhibitors. Anakinra competitively inhibits the binding of IL-1α and IL-1β to the IL-1 receptor (Alpay 2012). Rilonacept, known as IL-1 Trap (Economides 2003), is a soluble decoy receptor fusion protein that binds IL-1α and IL-1β, and as a result prevents IL-1 activation of cell surface receptors (Terkeltaub 2013).

Etanercept, infliximab and thalidomide are tumor necrosis factor (TNF) antagonists (Sampaio 1991; Seyahi 2006). The role of TNF antagonists in FMF has not been clarified exactly. However, the level of serum TNF-α increases during FMF attacks (Baykal 2003) and decreases with regular colchicine treatment (Kiraz 1998).

Finally, IFN-α is a natural species-specific immunomodulatory glycoprotein produced mainly by T and B lymphocytes. It increases macrophage and natural killer cell phagocytic activity as well as augmenting lymphocyte-specific cytotoxicity (Tweezer-Zaks 2008).

 

Why it is important to do this review

While there has been an evidence-based peer review of the use of colchicine for the treatment of FMF (WHO 2013), this important topic has not yet been systematically evaluated. Therefore, we are performing a Cochrane Systematic Review of available clinical evidence to evaluate the efficacy and safety of interventions for reducing inflammation in FMF.

 

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 interventions for reducing inflammation in FMF.

 

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 randomized controlled trials (RCTs), of both parallel and of cross-over design irrespective of publication status or language.

 

Types of participants

We will include people of any age, gender, and in any care setting, who are diagnosed with FMF. For adults, diagnosis will be based on the Tel Hashomer criteria (Livneh 1997; Soriano 2012) and for children on the Yalçinkaya criteria (Yalçinkaya 2009).

The Tel Hashomer criteria including major and minor criteria. The diagnosis of FMF is confirmed if two major criteria, or one major criterion and two minor ones are satisfied.

  • Major criteria include:

    1. recurrent febrile episodes with serositis;
    2. amyloidosis of AA-type detection;
    3. favourable response to colchicine treatment.

  • Minor criteria include:

    1. recurrent febrile episodes without signs of serositis;
    2. erysipelas-like erythema;
    3. FMF in a first-degree relative.

For the Yalçinkaya criteria please see the additional tables ( Table 1).

 

Types of interventions

We will compare active interventions (including colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, IFN-α and NSAIDs) with placebo or no treatment. We will also include comparisons of these drugs with each other. There are no restrictions on drug administration dose, frequency, intensity or duration.

 

Types of outcome measures

 

Primary outcomes

  1. Number of patients experiencing an attack
  2. Timing of FMF attacks
    1. duration of FMF attacks
    2. interval time between attacks
  3. Adverse drug reaction (ADR) of the following systems
    1. digestive system
    2. motor system
    3. circulatory system
    4. urogenital system
    5. nervous system
    6. respiratory system
    7. reproductive system
    8. endocrine system
    9. others, e.g. infections

 

Secondary outcomes

  1. Acute phase response
    1. erythrocyte sedimentation rate (ESR)
    2. white blood cell (WBC) count
    3. fibrinogen concentration
    4. C-reactive protein (CRP)
    5. serum amyloid A protein (SAA) concentration

 

Search methods for identification of studies

 

Electronic searches

We will search the following electronic databases to identify relevant RCTs:

  1. The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue);
  2. Ovid MEDLINE (1950 to present);
  3. Ovid EMBASE (1980 to present);
  4. Chinese Biomedical Literature Database (CBM) (1978 to present);
  5. China National Knowledge Infrastructure Database (CNKI) (1979 to present);
  6. Wan Fang database (1986 to present);
  7. VIP Database (1989 to present).

We will use the provisional search strategy detailed in the appendices in the Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 1). We will based our searches of MEDLINE and Embase on this search strategy and adapt them appropriately. We will also translate the search strategy appropriately for each Chinese database.

We will search the following clinical trials registries.

  1. ClinicalTrial.gov (http://clinicaltrials.gov/)
  2. International Standard Randomised Controlled Trial Number Register (ISRCTN) (http://www.controlled-trials.com/isrctn/)
  3. WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)
  4. Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org/cn/)

 

Searching other resources

We will search the references listed in relevant trials and reviews to identify any further relevant RCTs, as well as contact pharmaceutical companies who produce these drugs.

 

Data collection and analysis

 

Selection of studies

We will use EndNote X6 software to merge retrieved reports of each database and remove duplicate records of the same study (Endnote X6). Two review authors (BW, TX) will independently assess the titles and abstracts of studies to exclude obviously irrelevant reports. We will retrieve the full text copies of all potentially eligible reports, and review them in the light of the inclusion criteria. We will make final decisions on the included studies by cross-checking the results of the two review authors (BW, XY); we will consult a third review author (TX) if there are any disagreements. Where we identify multiple reports of the same study, we will extract the maximum amount of data from the multiple reports and identify one report as the primary reference.

 

Data extraction and management

We will undertake data extraction based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), using a data extraction form piloted by the Cochrane Cystic Fibrosis and Genetic Disorders Review Group and including the following information: general data (authors, publication year, contact information, etc.); baseline data (number of participants, age, gender, etc.); risk of bias assessment information (details of randomisation, allocation concealment, blinding, incomplete outcome data, etc.); interventions; duration of follow up; outcome measures; and results. We plan to contact the study authors for more information, if necessary. Two review authors (BW, XY) will independently extract and manage data from all included trials and resolve any disagreements by discussion. If these authors fail to reach an agreement, a third review author (TX) will act as arbiter.

We will not combine different drugs in a single comparison (e.g. any drug versus placebo) or different duration of treatment (e.g. up to and including one month, over one month and up to three months, over three months and up to 12 months, 12 months and over), instead we will present separate comparisons at different time-points.

 

Assessment of risk of bias in included studies

We will assess the risk of bias in the included studies using the methods recommended in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Two review authors (BW, XY) will independently evaluate the following seven items for each study: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other potential sources of bias. We will judge the risk of bias for each item as 'low risk', 'high risk' or 'unclear risk' following the assessment criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Appendix 2). Finally, we will produce a 'Risk of bias summary' and a 'Risk of bias' figure to present an assessment of the risk of bias. We will perform sensitivity analysis by removing studies at high risk of bias compared with all studies included (see below).

 

Measures of treatment effect

For dichotomous outcomes, we will present the risk ratios (RR) with their 95% confidence intervals (CIs) for each individual study. For continuous outcomes, we will present the mean differences (MDs) with their 95% CIs for individual studies. Where the same outcome is measured in a variety of ways among studies, we will use the standardised mean differences (SMD) with their 95% CIs.

 

Unit of analysis issues

We will consider individual participants as the unit of analysis. If possible, we will re-analyse any cluster-randomised trials identified by calculating the effective sample sizes with the intra-cluster coefficient (ICC) estimated externally from similar studies (Deeks 2011). If we are able to include any cross-over studies, we will use the data from the first period only (Elbourne 2002).

 

Dealing with missing data

We will attempt to contact the original study authors when essential data are missing from the study reports. If no reply is received after eight weeks, we will assume firstly that the missing participants experienced an attack and secondly that they did not experience an attack and will undertake an analysis based on each of these assumptions (best case and worst case scenario) respectively. We will examine the effects of these assumptions by performing a sensitivity analysis (Higgins 2011c).

 

Assessment of heterogeneity

Firstly, if clinical diversity exists between the studies (e.g. different drugs, or different treatment durations), we will not combine data from these studies. Secondly, for clinically homogeneous studies, we will perform a chi2 test, with P values less than 0.1 indicating significant statistical heterogeneity. In order to identify any heterogeneity we will initially visually assess the forest plots to identify any aberrant results. Furthermore, we plan to quantify heterogeneity not due to chance by using the I2 statistic (Higgins 2011d). A rough guide for the interpretation of I2 is as follows: 0% to 40% represents heterogeneity that might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% represents considerable heterogeneity (Deeks 2011).

 

Assessment of reporting biases

We will perform a comprehensive search for eligible RCTs to minimise reporting bias. If more than 10 studies are included, we will use funnel plots to assess publication bias (Sterne 2011). However, we are aware that there are also other reasons for funnel plot asymmetry other than publication bias, such as: poor methodological quality leading to spuriously inflated effects in smaller studies, true heterogeneity, artefactual or chance (Sterne 2011). We will also compare the study protocols with the final study reports to identify any outcomes that were measured but not reported. If study protocols are not available, we will compare the 'Methods' section of the published studies with the 'Results' section to identify any outcomes that were measured but not reported.

 

Data synthesis

We will analyse the data using RevMan 5.2 software provided by the Cochrane Collaboration (Review Manager (RevMan) 2012). We will use a fixed-effect model for the meta-analysis in the absence of clinical, methodological and statistical heterogeneity. If the I2 statistic is greater than zero, additionally, we will apply a random-effects model to see whether the conclusions differ, and any difference will be noted. If pooling is not possible or appropriate, we will present a narrative summary (Deeks 2011).

 

Subgroup analysis and investigation of heterogeneity

If sufficient studies are included (at least 10 studies), we will perform a subgroup analysis for different age groups (18 years and under old versus above 18 years of age) or different duration of treatment (e.g. up to and including one month, over one month and up to three months, over three months and up to 12 months, 12 months and over).

 

Sensitivity analysis

If we are able to include a sufficient number of RCTs (at least 10 studies), we will perform a sensitivity analysis for the primary outcomes to investigate the robustness of findings. We will conduct sensitivity analyses by comparing meta-analysis results of:

  1. removing cross-over studies compared with all included studies;
  2. removing studies at high risk of bias (e.g. one or more of the following items were at high risk: random sequence generation; allocation concealment; or selective reporting) compared with all included studies;
  3. assuming that missing participants had a positive outcome versus a negative one for the outcome of "number of patients experiencing an attack".

 

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

We would like to acknowledge the Cochrane Cystic Fibrosis and Genetic Disorders Group, especially Managing Editor Nikki Jahnke and the Trials Search Co-ordinator, for their help in preparing this protocol.

 

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. CENTRAL search strategy


Search strategy

#1 MeSH descriptor: [Familial Mediterranean Fever] explode all trees

#2 ((familial mediterranean fever) or (familial paroxysmal polyserositi*) or (FMF)):ti,ab,kw

#3 (#1 OR #2)

#4 MeSH descriptor: [Colchicine] explode all trees

#5 colchicine:ti,ab,kw

#6 MeSH descriptor: [Interleukin 1 Receptor Antagonist Protein] explode all trees

#7 (anakinra or rilonacept):ti,ab,kw

#8 (etanercept or infliximab):ti,ab,kw

#9 MeSH descriptor: [Interferon-alpha] explode all trees

#10 (interferon-alpha or INF-alpha or IFN-α):ti,ab,kw

#11 MeSH descriptor: [Thalidomide] explode all trees

#12 thalidomide:ti,ab,kw

#13 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12)

#14 (#3 AND #13)



 

Appendix 2. Criteria for judging risk of bias

 

Random sequence generation

'Low risk' of bias

The investigators describe a random component in the sequence generation process such as:

  • referring to a random number table;
  • using a computer random number generator;
  • coin tossing;
  • shuffling cards or envelopes;
  • throwing dice;
  • drawing of lots;
  • minimization.

'High risk' of bias

The investigators describe a non-random component in the sequence generation process, for example:

  • sequence generated by odd or even date of birth;
  • sequence generated by some rule based on date (or day) of admission;
  • sequence generated by some rule based on hospital or clinic record number;
  • allocation by judgement of the clinician;
  • allocation by preference of the participant;
  • allocation based on the results of a laboratory test or a series of tests;
  • allocation by availability of the intervention.

'Unclear risk' of bias

Insufficient information about the sequence generation process to permit judgement of low risk or high risk.

 

Allocation concealment

'Low risk' of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation:

  • central allocation (including telephone, web-based and pharmacy-controlled randomization);
  • sequentially numbered drug containers of identical appearance;
  • sequentially numbered, opaque, sealed envelopes.

'High risk' of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on:

  • using an open random allocation schedule (e.g. a list of random numbers);
  • assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered);
  • alternation or rotation;
  • date of birth;
  • case record number;
  • any other explicitly unconcealed procedure.

'Unclear risk' of bias
Insufficient information to permit judgement of low risk or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

 

Blinding of participants and personnel

'Low risk' of bias

Any one of the following:

  • no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding;
  • blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

'High risk' of bias

Any one of the following:

  • no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding;
  • blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

'Unclear risk' of bias

Any one of the following:

  • insufficient information to permit judgement of low risk or high risk;
  • the study did not address this outcome.

 

Blinding of outcome assessment

'Low risk' of bias

Any one of the following:

  • no blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding;
  • blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

'High risk' of bias

Any one of the following:

  • No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding;
  • Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

'Unclear risk' of bias

Any one of the following:

  • insufficient information to permit judgement of low risk or high risk;
  • the study did not address this outcome.

 

Incomplete outcome data

'Low risk' of bias

Any one of the following:

  • no missing outcome data;
  • reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);
  • missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;
  • for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate;
  • for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size;
  • missing data have been imputed using appropriate methods.

'High risk' of bias

Any one of the following:

  • reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups;
  • for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate;
  • for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;
  • 'as-treated' analysis done with substantial departure of the intervention received from that assigned at randomization;
  • potentially inappropriate application of simple imputation.

'Unclear risk' of bias

Any one of the following:

  • insufficient reporting of attrition or exclusions to permit judgement of low risk or high risk (e.g. number randomized not stated, no reasons for missing data provided);
  • the study did not address this outcome.

 

Selective reporting

'Low risk' of bias

Any of the following:

  • the study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way;
  • the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

'High risk' of bias

Any one of the following:

  • not all of the study's pre-specified primary outcomes have been reported;
  • one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified;
  • one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect);
  • one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis;
  • the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

'Unclear risk' of bias

Insufficient information to permit judgement of low risk or high risk. It is likely that the majority of studies will fall into this category.

 

Other potential sources of bias

'Low risk' of bias

The study appears to be free of other sources of bias.

'High risk' of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or
  • has been claimed to have been fraudulent; or
  • had some other problem.

'Unclear risk' of bias

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or
  • insufficient rationale or evidence that an identified problem will introduce bias

 

Appendix 3. Glossary



amyloidosisa variety of conditions where normally soluble proteins become insoluble and are deposited in various organs or tissues disrupting normal function

apoptosisa process of programmed cell death

colocalizeto occur together in the same cell

cytotoxicityprocess which results in cell damage or cell death

enterohepatic circulationthe circulation of drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver

exona sequence of DNA that codes information for protein synthesis that is transcribed to messenger RNA

homotypicof the same type or form

ileumthe final section of the small intestine

jejunumthe middle section of the small intestine

macrophagea type of white blood cell that removes dying or dead cells and cellular debris

microtubulefibrous, hollow rods, that function primarily to help support and shape the cell

oligomerizeto form a molecular complex that consists of a few monomer units

pericarditisinflammation of the thin sac-like membrane that surrounds the heart

peritonitisinflammation of the peritoneum, the thin tissue that lines the inner wall of the abdomen and covers most of the abdominal organs

phagocytic activitywhen a cell, such as a white blood cell, engulfs and absorbs waste material, harmful microorganisms, or other foreign bodies in the bloodstream and tissues

pleuritisinflammation of the membrane that covers the lungs and lines the chest cavity

proteolyticbreakdown of proteins into smaller polypeptides or amino acids

serositisinflammation of the tissues lining the lungs, heart, inner lining of the abdomen and organs within

synovitisinflammation of the membrane surrounding a joint

tubulinglobular proteins that make up microtubules



 

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

  1. Bin Wu developed the protocol, co-ordinated its development, completed the first draft, performed part of the writing and editing of the protocol, advised on the protocol and approved final version prior to submission.
  2. Ting Xu developed the protocol and co-ordinated its development, performed part of the writing and editing of the protocol, advised on the protocol and approved the final version prior to submission.
  3. Xi Yin co-ordinated the protocol development, made an intellectual contribution, advised on part of the protocol and approved the final version prior to submission.
  4. Youping Li conceived the review question, made an intellectual contribution, advised on the protocol and approved the final version prior to submission.

 

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

None known.

 

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

  • No sources of support provided, UK.

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
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