Treatment for inclusion body myositis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of pharmacological and non‐pharmacological treatment for skeletal muscle weakness, atrophy and inflammation in people with IBM. This will:
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determine whether there is any evidence for the benefit for any treatment; and
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provide recommendations for future trials in IBM.
Background
Description of the condition
Inclusion body myositis (IBM) is a late onset inflammatory muscle disease (myopathy) with a distinctive pattern of proximal and distal limb atrophy and weakness. IBM is considered to be the commonest acquired myopathy over the age of 50 years. In early published series, IBM has accounted for up to 28% of all idiopathic inflammatory myopathies, although the true proportion could be much higher (Lotz 1989). In the Netherlands, prevalence has been estimated at 4.9 per million inhabitants (Badrising 2000). Meanwhile, the prevalence of IBM in Western Australia has risen from 9.3 to 14.9 per million inhabitants between 2000 and 2008, a change attributed to improved case identification (Phillips 2000; Needham 2008). Prevalence adjusted for age over 50 years is higher, up to 51.3 per million population (Needham 2008).
IBM is usually a sporadic and isolated disorder that can be associated with secondary mitochondrial DNA abnormalities in excess of those seen with normal ageing (Oldfors 1995). In rare instances, typical IBM occurs in families (Amato 1998; Tateyama 2003); this familial IBM should not be confused with hereditary inclusion body myopathy (h‐IBM), which is not usually associated with inflammation and in which there may be mutations in the GNE gene (Huizing 2009). IBM is sometimes associated with a variety of connective tissue and autoimmune diseases, including rheumatoid arthritis (Soden 1994), vitamin B12 deficiency (Khraishi 1992), Sjögren's syndrome (Gutmann 1985; Khraishi 1992), chronic immune thrombocytopaenia (Riggs 1984), sarcoidosis (Danon 1986), collagen vascular disease (Lane 1985), and common variable immune deficiency (Dalakas 1995; Lindberg 1990).
To date, clinicopathologically‐defined criteria for sporadic IBM, as proposed by Griggs 1995 and revised by Benveniste 2010 and Hilton‐Jones 2010, have formed the basis for diagnostic criteria. Improved case ascertainment through clinical assessment has supported the application of clinically‐defined diagnostic criteria. However, for the purpose of reviewing the existing clinical trials, we will include those trials using clinicopathologically‐defined sporadic IBM, as defined by Griggs 1995, Benveniste 2010 or Hilton‐Jones 2010.
Potential outcome measures
The muscle atrophy and weakness of IBM usually follow a slowly progressive course with the mainstay of treatment being supportive at present. Natural history studies suggest that people with IBM can experience 3.5% to 5.2% annual decline in compound muscle strength graded manually and up to 28% annual decline in quadriceps muscle strength measured quantitatively (Cortese 2013; Cox 2011). Because of its characteristic pattern of muscle involvement, IBM may cause predictable functional difficulties. For example, weakness of the long (extrinsic) finger flexors can impair hand grip, while quadriceps weakness can cause knee instability, making rising from chairs, managing stairs and walking increasingly difficult. For the purpose of this review, it seemed reasonable to choose those outcome measures assessing the cardinal effects of IBM, namely muscle atrophy, weakness and functional impairment.
In terms of atrophy, the muscle mass can be measured in a number of ways, including (i) urinary creatinine excretion under controlled conditions, (ii) potassium isotope counting, (iii) magnetic resonance imaging (MRI), (iv) computerised tomography (CT), muscle imaging, and (v) dual energy x‐ray absorptiometry (DEXA). Muscle strength can be measured manually (referred to as manual muscle testing; MMT) and is commonly scored using the six‐point Medical Research Council (MRC) strength scale or modified MRC scale. Alternatively, the maximal voluntary isometric contraction or isokinetic muscle strength can be measured using a hand‐held or fixed myometer (referred to as quantitative muscle testing; QMT) and the results expressed in units of force (Newtons, kg or pounds). However, as with MMT, the selected muscles tested by QMT can vary; QMT sum scores are often expressed as the z score, which is the sum of the standard deviations from the mean for each muscle tested.
In terms of measuring functional impairment, there are a variety of single‐item tests, including timed walking tests, stair climb and rise from chair; we have chosen timed walking tests as appropriate measures for the patient population in this review. There are also questionnaire‐based, multi‐item rating scales, such as the IBM Functional Rating Scale (IBMFRS), that provide an overall score across different functional tasks (Jackson 2008). In choosing appropriate outcome measures for this review we also wanted to consider other Patient Reported Outcome Measures (PROMs) including symptom severity and quality of life, as well as adverse events associated with treatment. However, these outcome measures are not consistently applied across different muscle disease centres and trials at present.
A minimum time period can be specified for the primary outcome measure in relation to its sensitivity to change in a slowly progressive condition. Power calculations based upon available natural history data for muscle strength in IBM support a minimum trial length of six months (Rose 2001).
Description of the intervention
Interventions include pharmacological agents, dietary supplements and musculoskeletal surgery. Specific interventions excluded are the management of dysphagia and the role of exercise therapy for muscle disease, which are discussed in other Cochrane systematic reviews of interventions (Hill 2004; Voet 2013).
Why it is important to do this review
As the first systematic review of treatment for IBM, this Cochrane review aims to determine the evidence base for current treatment and identify dose‐responses where possible. The review findings may also be relevant to other neuromuscular and age‐related conditions in which muscle weakness, atrophy and inflammation are prominent symptoms.
Objectives
To assess the effects of pharmacological and non‐pharmacological treatment for skeletal muscle weakness, atrophy and inflammation in people with IBM. This will:
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determine whether there is any evidence for the benefit for any treatment; and
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provide recommendations for future trials in IBM.
Methods
Criteria for considering studies for this review
Types of studies
We will consider for inclusion randomised or quasi‐randomised trials of treatment in IBM (except for exercise therapy and dysphagia management) with no language restrictions. We will include comparisons of treatment versus placebo or any other treatment, considering each comparison separately. We will include studies reported as full‐text, those published as abstract only, and unpublished data.
Types of participants
All participants will be over 18 years in age and have a clinicopathologically‐defined diagnosis of IBM (Benveniste 2010; Griggs 1995; Hilton‐Jones 2010). We will specifically exclude people with familial IBM and hereditary inclusion body myopathy but we will include people who have connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials.
Types of interventions
We will include the following interventions.
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Immunosuppressive agents, e.g. prednisolone (and other corticosteroids), cyclophosphamide, chlorambucil, azathioprine, methotrexate (MTX), and ciclosporin.
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Immunomodulatory interventions, e.g. intravenous immunoglobulin (IVIg), leukopheresis, plasma exchange and immune‐targeted monoclonal antibodies.
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Antioxidants, e.g. vitamin E.
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Mitochondrial substrates, e.g. carnitine and ubiquinone.
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Anabolic steroids and muscle supplements.
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Other interventions except for exercise therapy and dysphagia management.
Therapies may be administered using various protocols including as single agents, combined therapy or sequential therapy. We will analyse different interventions separately.
Types of outcome measures
Primary outcomes
The primary outcome measure for this review will be percentage change in muscle strength (using MMT or QMT) from baseline at six months.
Secondary outcomes
Secondary outcome measures for this review will be the following.
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Percentage change from baseline in muscle strength (using MMT or QMT) at 12 months.
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Percentage change from baseline in muscle mass (by whatever method, e.g. MRI) at six months.
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Percentage change from baseline in hand grip strength at six months,
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Percentage change from baseline in timed walk (e.g. 10 metre or 6 minute) at six months.
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Significant adverse events from the intervention.
QMT will only be evaluated when MMT is not used for muscle testing in the trial. We will report results for other outcome measures used in trials under the 'Description of studies' section, although these will not form part of the analysis for this review.
Where relevant data are available we will also consider the cost‐effectiveness of interventions in the 'Discussion'.
Search methods for identification of studies
Electronic searches
We will identify trials from the Cochrane Neuromuscular Disease Group Specialized Register, which is maintained by the Trials Search Co‐ordinator for the Group. The Trials Search Co‐ordinator will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We will search all databases from their inception to the present, and we will impose no restriction on language of publication.
We will search ClinicalTrials.gov (www.clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials and completed unpublished studies using the search term 'inclusion body myositis'.
The MEDLINE search strategy is in Appendix 1.
Searching other resources
We will check references in the identified trials and contact trial authors to identify any additional published or unpublished data.
Data collection and analysis
Two of the review authors will extract data (KJ, KL or MR) and they will resolve any discrepancies in extraction by discussion. We will contact the authors of the trials to provide missing data where possible.
Selection of studies
At least two review authors (from among MW, JM, MR and KJ) will read the papers identified by the search strategy for studies that are eligible for inclusion. The review authors will independently confirm that studies are randomised or quasi‐randomised trials and that diagnostic criteria for IBM have been met.
Data extraction and management
At least two review authors (KL or MR, and KJ) will independently perform data extraction using a specially designed data extraction form. The authors of included trials will be contacted to provide missing data where possible. One author will check and enter data into RevMan (KL or MR); a second review author will check the data entry (KJ). There will be an independent data extraction by a non‐conflicted author or a member of the Cochrane Neuromuscular Disease Group editorial base if any review author has potential conflicts of interest, e.g. through involvement in an included study.
Assessment of risk of bias in included studies
At least two review authors (MR and KJ) will independently assess the risk of bias in randomised trials using the following criteria: sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective outcome reporting and other risk of bias. For each trial, the review authors will identify high, low or unclear risk of bias, according to criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use the 'unclear' rating when there is insufficient information to reach a judgement or when, despite knowing what occurred in the study, the risk of bias remains unclear. We will also examine whether studies include explicit diagnostic criteria, validation of outcome measurements, and power calculations to detect statistical benefit. Where there is uncertainty, we will contact trial authors for clarification. Where there are disagreements, the review authors will reach agreement on 'Risk of bias' assessment by consensus. We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review. To ensure dual independent risk of bias assessment, non‐conflicted review authors or members of the editorial base will assess risk of bias in the event of any potential conflict of interest.
Measures of treatment effect
We will analyse dichotomous data as risk ratios (RR) and risk differences with 95% confidence interval (CI). We will analyse continuous data as the mean difference, or standardised mean difference with 95% CI when outcomes are conceptually the same but measured in different ways. We will calculate a treatment effect through random‐effects meta‐analysis, using the Cochrane statistical package, Review Manager 5 (Revman 5) (RevMan 2014).
Unit of analysis issues
Compound muscle strength may be determined using different muscle groups and this could be a potential source of unit of analysis error. The carry‐over effect of sequential intervention is another potential source of unit of analysis error in cross‐over trials. There is also a possible learning effect in the primary outcome of interest, muscle strength, that may need to be considered in particular for cross‐over trials, due to sequential intervention.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is available as an abstract only). Where this is not possible, and missing data are thought to introduce serious bias, we will explore the impact of including such studies in the sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify any substantial unexplained heterogeneity we will report this and explore the possible causes by pre‐specified subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases.
Data synthesis
We will use a random‐effects model to assess average treatment effect on the assumption that included studies estimate different but related intervention effects. We will perform a sensitivity analysis with a fixed‐effect model to test the assumption of non‐identical data and to identify the presence of heterogeneity among included studies. If the review includes more than one comparison, which cannot be included in the same analysis, we will report the results for each comparison separately.
Summary of findings table
We will create a 'Summary of findings' table using the following outcomes.
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Percentage change in muscle strength (using MMT or QMT) from baseline at six months.
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Percentage change from baseline in muscle strength (using MMT or QMT) at 12 months.
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Percentage change from baseline in muscle mass (by whatever method, e.g. MRI) at six months.
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Percentage change from baseline in hand grip strength at six months.
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Percentage change from baseline in timed walk (e.g. 10 metre or 6 minute) at six months.
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Significant adverse events from the intervention.
We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using GRADEpro software (GRADEpro 2014). We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be performed to investigate the treatment effect in particular patient groups if there is sufficient detail to extract data about the different patient groups. Subgroup analysis will facilitate the investigation of heterogeneity using meta‐regression techniques.
Sensitivity analysis
We will perform a sensitivity analysis on the basis of 'Risk of bias' and to test for heterogeneity in the results.
