Rituximab for myasthenia gravis
Abstract
Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess:
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the safety and efficacy, as assessed by the effect on disease severity or functional ability and the burden of alternative treatment, of rituximab (including biosimilar variants) for the treatment of myasthenia gravis in adults; and
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outcomes and adverse effects between different patient subgroups, and treatment strategies, in order to aid treatment choice for individuals, and to inform policymakers about those most likely to benefit.
Background
Description of the condition
Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies (antibodies produced by a person's immune system that target other proteins in their body) bind to components of the post‐synaptic membrane at the neuromuscular junction, disrupting synaptic structure and impairing neuromuscular transmission, leading to fatigable muscle weakness (Engel 1971; Morgan 2006). The disease usually affects the external ocular muscles first, causing double vision and drooping upper eyelids (ptosis). Around three‐quarters of people with the condition go on to develop weakness of the neck, chewing, swallowing, proximal limb, and breathing muscles (Robertson 1998). This weakness can be life‐threatening due to respiratory failure or complications associated with severe exacerbations of disease (e.g. aspiration pneumonia, venous thromboembolism). Most cases are caused by autoantibodies to acetylcholine receptors (AChR), which occur in around 87% of people with the condition (Lindstrom 1976); the second most common antibody is one directed against muscle‐specific kinase (MuSK) (Fichtner 2020).
Myasthenia gravis can occur at any age. 'Early‐onset' MG is more common in women and is thought to be due to over‐activity of the immune system; the thymus gland is often larger than normal (thymic hyperplasia) in early‐onset MG (Vincent 2002). 'Late‐onset' MG is more common in men and is thought to be due to loss of immune tolerance (Stacy 2010). The cut‐off between early‐ and late‐onset MG is between 40 and 50 years of age; there is disagreement about the exact age, and it is likely that there is an overlap between the two disease subtypes. In around 10% of people with MG, the condition is associated with a tumour in the thymus (a thymoma) (Vincent 2002). In these cases, treatment is focused on removing this lesion. A prospective UK study found an average annual incidence rate (IR) of MG to be 17.6/1,000,000 (95% CI 10.7 to 28.6), which is rising in patients over 65 years of age (Maddison 2019).
Myasthenia gravis is diagnosed using a combination of clinical review, serological testing, and electrophysiological testing. Clinical review aims to elicit relevant symptoms in the history such as variable double vision, and fatigable weakness when chewing or swallowing, as well as signs on examination ‐ particularly fatigable weakness of eye movements, eyelid opening or closure, or the proximal limbs. Serological testing is performed for anti‐AChR and MuSK autoantibodies, and electrophysiological testing can identify a declining response with repetitive nerve stimulation or abnormal jitter on single nerve fibre testing. Depending on the mode of presentation (i.e. with either pure ocular or generalised disease) people with MG may come to the attention of ophthalmologists, neurologists, or general or acute physicians.
Acetylcholinesterase inhibitors are usually used as an initial treatment. If these do not improve symptoms, then immunosuppression ‐ initially with prednisolone ‐ is used. If high doses of prednisolone are required to maintain clinical stability, this is followed by the addition of a steroid‐sparing agent, such as azathioprine or mycophenolate mofetil (Sussman 2015). For severe exacerbations of generalised disease, intravenous immunoglobulin (IVIg) or plasma exchange may be required. Rituximab can be used for those who do not respond to standard acute or long‐term treatments. If thymoma is present it should be removed, and may require further treatment such as radiotherapy. In addition, in those with AChR MG without thymoma, there is evidence that surgical removal of the thymus (thymectomy) reduces treatment requirements in those under the age of 65 years (Wolfe 2016).
Many people with MG do not achieve full pharmacological remission, and around 10% are refractory to conventional immunotherapy, although estimates vary significantly, and there is no internationally agreed definition of refractory disease (Suh 2013; Silvestri 2014; Santos 2019). Mortality is estimated to occur at a rate of 0.1 to 0.9 per million person‐years (Carr 2010), and drug‐related adverse effects, especially with corticosteroids, are common. Permanent weakness can occur due to steroid‐induced myopathy, or, in uncontrolled disease, long‐term activation of the complement system which can lead to muscle damage (Zamecnik 2009; Nakano 1993). Healthcare utilisation in this refractory cohort is high (Graham 2018; Harris 2019).
Description of the intervention
Rituximab is a chimeric mouse/human anti‐CD20 monoclonal antibody. It has been used since 1997 in oncology (Maloney 1997), particularly for B‐cell lymphomas. Subsequently, its use expanded to autoimmune diseases, including rheumatoid arthritis, immune thrombocytopenia, pemphigus vulgaris, and neuroinflammatory disorders including neuromyelitis optica, neuropathies and myopathies as well as MG (MacIsaac 2018). The first case report of successful use of rituximab for MG was in a patient who developed MG following a bone marrow transplant for acute nonlymphocytic leukaemia (Zaja 2000), with the first prospective case series of six patients reported in 2008 (Tandan 2008). Following this, rituximab has increasingly been used as a treatment for both refractory and severe exacerbations of generalised MG (Iorio 2015; Lebrun 2009; Nowak 2011; Sudulagunta 2016; Tandan 2017). Current international consensus guidelines support its use for people with MuSK‐MG who have an unsatisfactory response to initial immunotherapy, but there is uncertainty regarding its use in people with AChR‐MG (Narayanaswami 2021).
Rituximab is administered by intravenous infusion, usually as two doses given a fortnight apart, although various dosage strategies may be followed, each borrowed from other autoimmune diseases such as rheumatoid arthritis. A 'day case' admission to hospital is usually required for each infusion. Re‐treatment may be needed, either for relapsing disease or, potentially, in response to increasing circulating B‐cell counts (Whittam 2019). A neurologist with a special interest in neuro‐inflammatory disorders usually oversees treatment, with the support of pharmacists, specialist nurses, and immunologists, where appropriate.
Key issues when considering the commencement of rituximab therapy include the risk of infection, contraindications (such as severe heart failure), pregnancy, breastfeeding and contraception, and the person's ability to participate actively in safety monitoring. As with similar medications, the use of rituximab carries the risk of reactivation of latent infections, including tuberculosis and viral hepatitis, and the potential for opportunistic infections to occur. One of the most serious risks is of progressive multifocal leukoencephalopathy, caused by activation of the John Cunningham (JC) virus within the central nervous system. Although this is usually fatal, occurrence after rituximab treatment is very rare. Immunisation against pneumococcus, influenza, and COVID‐19, if not already given, should be given ideally at least two to four weeks before treatment (Department of Health 2021; Papp 2019), although this is not possible in acute situations. If time allows, individuals should have varicella‐zoster antibodies assessed, and, if not immune, receive vaccination more than four weeks prior to rituximab initiation (Rubin 2013); additionally, household contacts without immunity to varicella‐zoster should also be vaccinated (Department of Health 2021).
Co‐administration of other immunosuppressive agents is often avoided to reduce the risk of infection, but there is variability in practice due to a lack of evidence for best practice. Other risks of rituximab treatment include infusion reactions, cardiac events, secondary immunoglobulin deficiency, cytopenias, and posterior reversible encephalopathy syndrome (European Medicines Agency 2021).
How the intervention might work
Rituximab acts rapidly to deplete cells expressing cluster differentiation (CD)‐20 transmembrane proteins, which are all circulating B‐cells, but not those terminally differentiated into antibody‐producing plasma cells which reside in lymphoid tissue and bone marrow. Binding activates a number of auto‐destructive responses, leading to B‐cell depletion (Whittam 2019). IgG4 titres are reduced, but not total IgG, which may explain the preferential response in MuSK‐MG, which is an IgG4‐mediated disease (Marino 2020).
In addition to B cell depletion, other beneficial effects of rituximab include secondary changes in T‐cell function, such as induction of immunoregulatory T cells, and restoring the balance between effector and regulatory B cells (Cooper 2010).
Why it is important to do this review
Rituximab has recently been approved for the use in MG by the National Health Service in England, but it remains unlicensed for this indication (NHS England). Consensus has not been reached on dosing schedule, biosimilar use, treatment duration, efficacy and safety monitoring, and benefits to specific MG subgroups. Despite this, usage of rituximab is increasing, and this trend is likely to continue as 'biosimilar' versions of rituximab have reduced drug costs, alongside a global shortage of IVIg (Nawrat 2020). In addition, as newer ‐ and therefore ‐ more expensive, therapies become available for MG, it will be vital to understand the efficacy and safety of rituximab in order to determine its place in the management of MG. These newer agents include neonatal Fc receptor blockers, such as efgartigimod, and complement inhibitors such as eculizumab and ravalizumab, which have both been recently approved for use in the USA for AChR MG (FDA 2022; FDA 2021; Mantegazza 2020).
Objectives
To assess:
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the safety and efficacy, as assessed by the effect on disease severity or functional ability and the burden of alternative treatment, of rituximab (including biosimilar variants) for the treatment of myasthenia gravis in adults; and
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outcomes and adverse effects between different patient subgroups, and treatment strategies, in order to aid treatment choice for individuals, and to inform policymakers about those most likely to benefit.
Methods
Criteria for considering studies for this review
Types of studies
We will only include randomised controlled trials (RCTs) and quasi‐RCTs. Quasi‐randomised trials are studies that allocate participants to groups using methods that are partly systematic, for example by alternation, use of a case record number, or date of attendance.
We will include studies reported in full text, those published as abstracts only, and unpublished data available from clinical trial registries or provided directly by researchers. There will be no restrictions regarding language of publication. Analysis will be limited to publications relating to male and female adults (aged 18 or over).
Cross‐over trials, where individuals undergo more than one intervention, are eligible for inclusion. We will exclude cluster RCTs, as the unit of analysis for all studies included in the review is the individual participant. We will exclude any studies that are not randomised or quasi‐randomised as they are generally at higher risk of bias.
Types of participants
We will apply the following eligibility criteria for participants.
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Diagnostic criteria: adults diagnosed with MG according to any diagnostic/classification criteria.
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Disease severity: any degree of severity (according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification). Analysis will include pooled data and subgroup analysis as per these groups where possible.
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Disease subtypes: all MG subtypes according to MG relevant autoantibody status (including AChR, MuSK and seronegative etc.), age of onset (early or late onset), thymic status (e.g. thymoma associated/non‐thymoma associated) or clinical phenotype (e.g. localised or generalised disease). Analysis will include pooled data and subgroup analysis as per these groups where possible.
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Previous treatment and disease duration: we will include participants who have received any previous MG treatments, including IVIg, steroid‐sparing immunosuppressants and plasma exchange, and any disease duration. Analysis will include pooled data and subgroup analysis (e.g. treatment naive or previously treated) where possible.
We will exclude participants with the following co‐morbidities/characteristics.
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Less than 16 years of age: juvenile myasthenia gravis is very rare, has higher rates of spontaneous remission than adult myasthenia gravis, and initial management is likely to differ from general adult practice, therefore, response to rituximab may not be comparable (O'Connell 2020). In addition, the authors of this review have no experience of managing paediatric patients.
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Previous history of rituximab treatment: those who have been given rituximab previously for an indication other than MG.
Types of interventions
Rituximab (including biosimilar variants) administered according to any dosing regimen.
The analysis will include pooled data and subgroup analysis (e.g. total dose over the first month low (< 1 g or ≤ 375 mg/m2) versus high (≥ 1 g or > 375 mg/m2), and whether repeated doses at a later time point were given or not), where possible.
Comparisons (considered individually) will include:
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placebo;
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no treatment; or
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an alternative immunosuppressive or immunomodulatory treatment.
We will include co‐interventions (e.g. prednisolone), if they are allocated to each group equally.
Biosimilar variants include Rituxan, Truxima, Ruxience, Riabni, Rixathon, Riximyo, Ritemiva, and Rituzena.
Types of outcome measures
The outcomes listed here are not eligibility criteria for this review, but are outcomes of interest within any studies that are included. Given the variable duration of studies, we will consider any and all post‐intervention time points, but will divide these into short‐term (2 months or less), medium‐term (over 2 months to 9 months), or long‐term (over 9 months). We will consider all outcomes at all of these time points, if data are available. Rituximab probably works over weeks to months, and may have long‐lasting effects due to a 'resetting' of the B‐cell population.
Primary outcomes
Improvement in symptom severity or functional ability: measured and analysed as continuous data by mean change in score from baseline. We will report long‐term time points (over 9 months) as our primary time point. If reports provide appropriate data, we will also analyse the data dichotomously, to assess whether or not a significant improvement is seen. This will allow us to evaluate the proportion of responders, as well as the degree of response.
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Quantitative MG (QMG) score: whilst mostly focusing on muscle strength, the QMG is the most widely used validated measure in clinical trials in MG. A clinically significant improvement is shown by a ≥ 2‐point reduction of mean score between baseline and post‐rituximab treatment in mild to moderate disease (QMG 0‐16), or a ≥ 3‐point reduction for severe MG (QMG >16) (Katzberg 2014).
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MG‐Activities of Daily Living (ADL) score: this outcome is important to patients. A clinical improvement is indicated by a 2‐point improvement in score from baseline to post‐rituximab treatment (Muppidi 2011).
Reduction in burden of alternative treatment: we will report the following measures independently if data are available.
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Steroid‐sparing effect: measured and analysed as a risk ratio of dichotomous data; whether or not an average dose of prednisolone ≤ 10 mg/day is achieved, which is a clinically meaningful target. This may require obtaining individual participant data (IPD), but if this is not possible, we will perform a narrative synthesis.
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Relapse requiring rescue therapy (including IVIg and plasma exchange): comparison of rate of requirement for rescue therapy to treat worsening MG, measured and analysed as a rate ratio.
Secondary outcomes
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Improvement in symptom severity or functional ability as described under Primary outcomes, measured at short term (2 months or less) and medium term (over 2 months to 9 months). In addition, we will analyse the MG Composite (MGC) score in the short, medium and long term in the same way:
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MGC score: a clinically significant improvement is defined as a ≥ 3‐point reduction in mean change in the MGC score, compared between baseline and post‐rituximab treatment (Burns 2010). This tool combines measures of muscle strength with activities of daily living, and is the outcome measure of treatment response recommended by the Task Force on MG Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (Benatar 2012; Jaretzki 2000), however, it is not used in all MG trials.
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Quality of life: assessed by MG‐quality of life (MG‐QoL) score, as a change from baseline to post‐rituximab treatment, measured and analysed as continuous data (Burns 2011).
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Hospital admissions: comparison of the rate of hospitalisation due to MG pre‐ and post‐rituximab treatment in the rituximab‐treated group versus the control group, measured and analysed as a rate ratio.
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Adverse effects: comparison of the proportion of participants experiencing any adverse effects in the rituximab‐treated group versus the control group at any time after the introduction of treatment. Type of adverse event, timing in relation to rituximab treatment, and potential causality will be collected if available. Assessment of characteristics of participants experiencing adverse events (e.g. type of MG, previous treatments etc.) will be made where possible. Adverse events will be analysed as risk ratios and categorised as follows:
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any adverse event;
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treatment‐related adverse events;
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adverse events which lead to discontinuation of treatment;
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serious adverse events (those which are fatal, life‐threatening, or require prolonged hospitalisation).
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Antibody titre: change in antibody titre from baseline to the specified follow‐up time‐point(s). We will report data separately for each antibody subtype, and measure and analyse the outcome as continuous data.
Search methods for identification of studies
Electronic searches
The Cochrane Neuromuscular Information Specialist will search the following databases:
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Cochrane Neuromuscular Specialised Register via the Cochrane Register of Studies (CRS‐Web);
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Cochrane Central Register of Controlled Trials (CENTRAL) via CRS‐Web;
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MEDLINE (1946 to present; Appendix 1);
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Embase (1974 to present).
All databases will be searched from their inception to the present, and we will impose no restriction on language of publication.
We will search the following trials registries for ongoing studies:
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WHO trials registry (ICTRP; apps.who.int/trialsearch/).
Where unpublished trials are identified from these sources, the principal investigator will be contacted and asked to provide the relevant data.
Searching other resources
We will search reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information.
Data collection and analysis
Selection of studies
We will complete the following using the Covidence online system (Covidence).
Two of three review authors (from KCD, JBL, and YSK) will independently screen titles and abstracts of all the potential studies we identify as a result of the search for inclusion and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports or publications and two of three review authors (from KCD, JBL, and YSK) will independently screen the full text and identify studies for inclusion. We will identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (either JDS or JM). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2015) and 'Characteristics of excluded studies' table.
Data extraction and management
We will use data extraction tools within Covidence to record study characteristics and outcome data (Covidence). This process will initially be piloted on at least one study in the review. One review author (KCD, JBL or YSK) will extract study characteristics from included studies. We will extract the following study characteristics:
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study design and setting;
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characteristics of participants (e.g. disease severity and age);
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eligibility criteria;
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intervention details;
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outcomes assessed;
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source(s) of study funding; and
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any conflicts of interest amongst investigators.
These details will be checked by a second author (one of KCD, JBL or YSK).
Two of three review authors (from KCD, JBL, and YSK) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person (JDS or JM). One review author (KCD) will transfer data into Review Manager (Review Manager 2020 or Review Manager Web). A second author will check the outcome data entries (YSK or JBL). A second review author (YSK or JBL) will spot‐check study characteristics for accuracy against the trial report.
When reports require translation, the translator will extract data directly using a data extraction form, or authors will extract data from the translation provided. Where possible a review author will check numerical data in the translation against the study report.
Assessment of risk of bias in included studies
Two review authors (one of either KCD or YSK, and one of either JBL, JDS or JM) will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We will resolve any disagreements by discussion or by involving another author not previously involved in assessing that particular study. We will assess the risk of bias according to the following domains.
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Random sequence generation
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Allocation concealment
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Blinding of participants and personnel
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Blinding of outcome assessment
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Incomplete outcome data
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Selective outcome reporting
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgement in the risk of bias table. We will summarise the risk of bias judgements across different studies for each of the domains listed.
We will attempt to identify study protocols. We will use the ORBIT (Observatory for Responsible Research and Innovation in ICT) framework to examine the impact of selective reporting of outcomes (ORBIT; outcome-reporting-bias.org/BenefitOutcomes).
Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the risk of bias table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome. We will make summary assessments of the risk of bias for each important outcome (across domains) within and across studies (Higgins 2017).
Assessment of bias in conducting the systematic review
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 full review.
Measures of treatment effect
We will analyse dichotomous data (i.e. data with one of two possible values) as risk ratios (RR) for significant clinical improvement in QMG, MGC or MG‐ADL (if dichotomous data are available), steroid sparing effect and adverse events.
We will analyse continuous data (for QMG, MGC, MG‐ADL, quality of life, and antibody titres) as mean difference. We do not anticipate combining different scales and are unlikely to report standardised mean differences (for results across studies with continuous outcomes that are conceptually the same but measured in different ways). We will report corresponding 95% confidence intervals (CIs). We will enter data presented as a scale with a consistent direction of effect.
We will report relapse requiring rescue therapy and hospital admissions as rate ratios with 95% CI.
We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
Unit of analysis issues
Where multiple trial arms are reported in a single trial, we will include only the treatment arms relevant to the review topic. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will follow guidance in Chapter 23 of The Cochrane Handbook for Systematic Reviews of Interventions to avoid double‐counting (Higgins 2022a). Our preferred approach will be to combine intervention groups if clinically appropriate.
Cluster RCTs are not eligible for inclusion as the unit of analysis is the cluster and not individual participants. If we identify cross‐over studies, we will use the first period of data only.
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 the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity amongst the trials in each analysis. If we identify substantial unexplained heterogeneity we will report it and explore possible causes by prespecified subgroup analysis. We will use the rough guide to interpretation as outlined in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions, as follows:
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
We will avoid the use of absolute cut‐off values, but interpret I²in relation to the size and direction of effects and strength of evidence for heterogeneity (e.g. P value from the Chi2 test, or CI for I²) (Deeks 2022).
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 in Review Manager (Review Manager 2020; Review Manager Web), as this is usually a more conservative approach. Where analyses include both small and large studies, we will perform a sensitivity analysis to determine whether their results are systematically different, since in these circumstances, use of a random‐effects meta‐analysis will exacerbate the effects of the bias.
If the review includes more than one comparison, and they cannot be included in the same analysis, we will report the results for each comparison separately.
We will combine the natural logarithms of the rate ratios across studies using the generic inverse‐variance method (Deeks 2022).
We will consider comparison interventions (placebo, no treatment, or an alternative treatment) in separate analyses.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses where possible.
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Disease subtype
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Early‐onset versus late‐onset MG (using a cut‐off age of 45 years as per Akaishi 2016)
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Antibody status: comparison of AChR, MuSK, other relevant autoantibodies and seronegative MG groups
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Thymoma‐associated versus non‐thymoma‐associated MG
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Localised (e.g. ocular) versus generalised MG
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Disease severity: comparison of pre‐treatment mild (MGFA I or II, or if MGFA not recorded QMG 0‐9), moderate (MGFA III or if not recorded QMG 10‐16), and severe (MGFA IV or V, or if not recorded QMG >16) disease groups
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Previous treatment
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Treatment‐naive versus refractory MG
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Thymectomy versus no thymectomy (non‐thymoma‐associated MG only)
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Steroid alone versus steroids and other immunosuppressive agent versus steroid‐sparing immunosuppression alone
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Disease duration: (under two years versus over two years)
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Treatment dose
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Total dose over the first month: low (< 1 g or ≤ 375 mg/m2) versus high (≥ 1 g or > 375 mg/m2)
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Whether repeated doses at a later time point were given or not
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In subgroup analyses, we will use the same outcomes as we use in the main analyses. We will use the formal test for subgroup interactions in Review Manager (Review Manager 2020 or Review Manager Web).
Sensitivity analysis
We plan to carry out sensitivity analyses, removing the following from the primary outcome analyses:
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unpublished studies (if there are any);
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studies at high overall risk of bias in any domain; and
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studies that recruited only a subset of people with MG.
We will report sensitivity analyses in a summary table.
To assess the effects of study size, we will compare our results from a random‐effects model with those using a fixed‐effect model which weights according to the size of included studies.
To ensure people have not been included in more than one study, we will review manuscripts for information relating to inclusion of participants in other studies. If there are any uncertainties, we will contact the authors for clarification.
Reaching conclusions
We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.
Summary of findings and assessment of the certainty of the evidence
We will use GRADEpro GDT to create one or more summary of findings tables (GRADEpro 2021). With reference to each studied control group, we will construct separate tables, if data are available. We will prioritise the comparison to placebo as our main summary of findings table, and we will present the following outcomes, as defined under Types of outcome measures, and measured in the long term (over nine months):
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QMG score;
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MG‐ADL score;
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MGC score;
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steroid‐sparing effect;
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relapse requiring rescue therapy;
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quality of life; and
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adverse effects.
In addition, we will create separate tables with GRADE assessments for all specified outcomes and the following time frames and include them as additional tables:
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short term: 2 months or less;
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medium term: over 2 months to 9 months; and
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long term: over 9 months (outcomes not presented in the prioritised summary of findings table).
If the study reports multiple time points within a time frame, we will report the latest time point that falls within each time frame and use this in the analysis.
Two of three review authors (KCD, JBL, YSK) will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to independently assess the certainty of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2022). We will resolve any disagreements by discussion or by involving another author (JDS or JM). We will assess the certainty of evidence according to the GRADE criteria. We will consider RCTs as high certainty evidence if the five factors above are not present to any serious degree, but may downgrade the certainty to moderate, low or very low if they are present. We will downgrade evidence once if a GRADE consideration is serious and twice if very serious. We will justify all decisions to downgrade or upgrade the certainty of the evidence using footnotes and make comments to aid readers' understanding of the review where necessary.
