FcRn inhibitors for myasthenia gravis

Objectives

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

To evaluate the benefits and harms of FcRn inhibitors for the maintenance treatment of myasthenia gravis in adult participants compared with control treatment (placebo, standard‐of‐care therapy, an alternative FcRn inhibitor, or an alternative immunomodulatory therapy).

• We will evaluate the efficacy of the treatment by the effect on disease severity and functional impairment, as assessed using a measurement tool validated for use in myasthenia gravis. Where possible, we will assess whether the effects of FcRn inhibitors differ according to different participant subgroups or different treatment regimens, or both.

• These data will be used to inform policymakers on the participant subgroups most likely to benefit from treatment and the most efficacious treatment regimen.

Background

Description of the condition

Myasthenia gravis (MG) is a neurological disorder affecting the area of the body where the nerve cells connect to the muscles, a region known as the neuromuscular junction (NMJ) [1]. MG is caused by an autoimmune process, where the body’s immune system produces antibodies against components of the NMJ. This causes muscle weakness, which often becomes worse the more the muscle is used (a process known as fatigability). Indeed, those affected often note that the weakness is worse towards the end of the day. The muscles typically affected by MG are those of the eyes (ocular) and throat (bulbar), respiratory muscles, and limb muscles [2]. MG of the ocular muscles results in drooping of the eyelids (ptosis) and double vision (diplopia), while bulbar MG causes problems with speech and swallowing. If respiratory muscles are involved, there can be difficulty with breathing, while MG in the limbs affects walking and movement. While MG remains a rare disorder, the incidence and prevalence are increasing, particularly in the elderly [3]. The incidence of MG is currently 5.3 per one million person‐years, and the prevalence is 77.7 per one million person‐years [4].

MG can be classified in several ways: according to disease onset (early versus late), clinical presentation of the disease (ocular or generalised disease), the antibody target in the NMJ, and whether there is involvement of the thymus gland. Disease onset in MG can be divided into early onset (typically aged < 45 years) and late onset (age > 45 years) [5]. Early‐onset MG is more common in females and those with thymus gland abnormalities, while late‐onset disease is more common in males [6, 7]. The mechanism of disease is believed to differ between the two types: the production of autoantibodies in early‐onset disease is due to overactivity of the immune system, while late‐onset disease is caused by loss of immune tolerance in a previously normal immune system [6, 7]. Both mechanisms result in the production of autoantibodies to components of the NMJ. The most common antibody subtype is the acetylcholine receptor (AChR), which is found in 85% of affected individuals. Other antibody targets are much less common and include muscle‐specific kinase (MuSK) (5% of affected individuals) and lipoprotein‐related protein (LRP4) (2% of affected individuals) [7]. In approximately 5% to 7% of people with clinical MG no autoantibody is identified; these individuals are classified as seronegative.

In some people with MG the development of the disease is due to abnormalities of the thymus, a gland that is involved in the development and monitoring of the immune system. A tumour of the thymus (known as a thymoma) is found in 15% of people with MG. Unlike thymic carcinoma (an aggressive cancer of the thymus gland), thymomas are usually slow growing and do not tend to spread from the thymus gland to other parts of the body [8]. Treatment of people with MG and thymoma involves surgery to remove the thymoma, which can result in improvement in MG symptoms [9, 10].

The clinical presentations of MG are grouped according to which areas of the body are affected. MG is typically classified as either ocular (eye involvement only) or generalised disease, where several areas of the body are affected (e.g. ocular, bulbar, respiratory and/or limb involvement) [6, 7]. Some people with ocular MG will continue to have eye involvement only; however, most will progress to generalised MG during the course of the disease [6, 7].

The approach to diagnosis in MG is multimodal and warrants evaluation by a specialist neurologist. Patients will require a clinical assessment, including a full history and examination to detect signs of fatigable weakness. Investigations will include serological (blood) testing for autoantibodies (namely AChR and MuSK), while neurophysiology (nerve tests) can be used to demonstrate a waning/decrement in the response of the muscles to repetitive stimulation [11]. In all cases of suspected MG, a computed tomography (CT) scan of the chest should be done to check for a thymoma. Additional investigations (e.g. brain or spine imaging) may be warranted for patients with negative serology and neurophysiology testing, to rule out brain or spinal causes of muscle weakness [11].

An MG crisis is defined as a sudden worsening of MG symptoms that is life‐threatening and involves the respiratory muscles, which can result in the affected person requiring intubation and ventilation in an intensive care unit [11]. People in MG crisis may be treated with intravenous immunoglobulin (IVIg, which comprises donated antibodies that can help dampen down the immune response) or plasma exchange (a process whereby the blood plasma, the part of the blood that contains antibodies, is removed and replaced) [11]. These therapies work within days to reduce the effects of autoantibodies, but are only effective for four to six weeks. Due to the potential risks, high cost, and low availability of these therapies, they are not suitable for long‐term therapy.

The initial management of MG not in crisis is typically with the medication pyridostigmine. In those who remain symptomatic despite treatment with pyridostigmine, prednisolone (a steroid treatment) is often used as add‐on therapy [11, 12]. In people with MG who do not achieve remission (resolution of their symptoms) with prednisolone therapy, or experience a relapse (re‐emergence of their symptoms) on prednisolone withdrawal, immunosuppressive medications that dampen down the immune response, such as azathioprine, are used [11, 12]. Other immunosuppressive therapies used for people with MG are mycophenolate mofetil, methotrexate, and ciclosporin. Rituximab is an antibody treatment that is targeted against a receptor called CD20. CD20 receptors are found on the surface of B cells, which are the cells of the immune system that make antibodies. In the UK, rituximab is used in the treatment of refractory MG (where symptoms of MG persist despite treatment). Surgery is warranted for people with a thymoma, and should also be considered for those without a thymoma who are aged less than 65 years and AChR antibody‐positive, as a thymectomy has been suggested to reduce the medication burden in this subset of people with MG [13].

There remains a substantial unmet need in the treatment of MG. While 70% to 80% of individuals will respond to initial treatment, people with MG are often dependent on ongoing treatment to keep their disease in remission (known as maintenance treatment) [14]. There are several well‐documented side effects associated with steroids and immunosuppressive therapy, which can accumulate over time and increase the morbidity (the burden of symptoms associated with a disease) and mortality (death) associated with MG. Further, there is a not insignificant subset of people (around 15%) with MG that do not respond to current treatments (known as treatment‐refractory disease) [15]. Individuals with treatment‐refractory MG have poorly controlled symptoms, resulting in a high symptom burden and frequent MG crises, which result in inpatient admissions for urgent treatment. Therefore, in both individuals with treatment‐responsive and treatment‐refractory disease, there is a high morbidity associated with the MG disease process and current treatments, which includes a negative impact on work, family dynamics, and quality of life. The management of MG and MG crises is also a significant burden on the healthcare system and the economy [14].

Description of the intervention and how it might work

Antibodies are a critical component of the adaptive immune system. There are several different subtypes of antibodies, with the most common being immunoglobulin G (IgG), constituting 70% to 80% of total antibodies in the body [16, 17]. Antibodies of the immune system have two distinct functional parts: the fragment of antigen binding (Fab) domain and the constant fragment crystallisable (Fc) domain. The Fab domain is highly variable between different antibodies and acts to recognise and bind foreign molecules. The Fc domain is constant between antibodies and acts to signal to the rest of the immune system through binding to various receptors found on the surface of immune system cells, including the Fc gamma receptor (FcγR) [16, 17]. The FcγRs are a diverse family of receptors that can be found in various locations in the body and have different affinities (strength of binding) for different subclasses of IgG antibodies. Neonatal FcR (FcRn) is a structurally unique subtype of the FcγR that is expressed in a wide variety of body tissues. FcRn can bind IgG and prevent its breakdown, thus prolonging the activity of IgG [16, 17]. Therefore, targeting the FcRn in MG is a potential mechanism to inhibit autoantibody‐induced effects in the NMJ, thereby improving symptoms. Several FcRn‐blocking agents have been developed to date; these include efgartigimod, rozanolixizumab, nipocalimab, and batoclimab. The intended recipients of FcRn‐blocking agents are people with AChR or MuSK‐positive generalised MG, as these forms of MG are known to be caused by autoantibodies of primarily the IgG class [16]. FcRn inhibitors are not currently available in the UK, but are approved for use in the European Union as an add‐on to standard therapy for the maintenance treatment of individuals with generalised MG [18].

Efgartigimod is a humanised IgG1 Fc fragment that is given at a dose of 10 mg/kg per week intravenously (IV) for four weeks [16, 17]. Subsequent four‐week cycles can be administered, according to response, at least seven weeks from the start of the previous cycle. The ADAPT multicentre randomised controlled trial (RCT) showed that there were significantly higher rates of response (as measured by the Myasthenia Gravis Activities of Daily Living (MG‐ADL) score) in people treated with efgartigimod compared with placebo treatment (68% versus 30% of participants, P < 0.001)[18]. Efgartigimod was approved by the US Food and Drug Administration (FDA) in 2021 and the European Medicines Agency (EMA) in 2022 for use in people with AChR antibody‐positive generalised MG [19, 20]. Trials of efgartigimod in children with MG are ongoing [21, 22, 23].

Rozanolixizumab is a humanised monoclonal IgG4 antibody that is administered subcutaneously (SC; into the skin) at a dose according to body weight [16, 17]. Rozanolixizumab is generally given once weekly for six weeks, with subsequent treatment cycles if warranted depending on the clinical response. The MycarinG multicentre RCT demonstrated significant improvements in the MG‐ADL score from baseline in people treated with either a 7 mg/kg or 10 mg/kg dose of rozanolixizumab versus placebo treatment (P < 0.001) [24]. In 2023, rozanolixizumab was approved by the FDA for the treatment of people with generalised MG who are AChR or MuSK antibody‐positive [25]. Efgartigimod was approved in Japan in 2022 for use in adults with difficult‐to‐treat generalised MG, irrespective of their antibody status [26].

Nipocalimab is a humanised glycosylated monoclonal IgG1 antibody that is given IV at a dose of 30 mg/kg at the first infusion, then 15 mg/kg thereafter every two weeks [16, 17]. The Phase 2 Vivacity‐MG study showed a statistically significant change from baseline in MG‐ADL score to day 57 with nipocalimab treatment (P = 0.031) [27]. A phase III trial is under way to compare the efficacy and safety of nipocalimab versus placebo treatment in adults with generalised MG [28]. Nipocalimab is not yet approved for use in the USA or the European Union for people with MG. A study of nipocalimab in children with MG is ongoing [29].

Batoclimab is a humanised monoclonal IgG1 antibody that can be delivered IV or SC [16]. A phase 2a RCT showed that participants treated with batoclimab had overall greater improvements in MG‐ADL scores at six weeks compared with placebo, but this did not reach clinical significance, likely due to small numbers of participants in the trial [30]. Batoclimab is not yet approved for use in MG, but a phase III trial of batoclimab versus placebo treatment is ongoing in adults with generalised MG [31].

FcRn inhibitors such as efgartigimod may also be effective as a rescue therapy for individuals in MG crisis. However, the evidence for efgartigimod in MG crisis is restricted to case reports [32, 33, 34, 35, 36], case series [37, 38], and small comparative studies [39, 40]. The use of FcRn inhibitors as a treatment in MG crisis is outside the scope of this literature review.

There are safety concerns to consider with the use of FcRn inhibitors. There have been reports of infusion reactions such as rash or pruritus (itching), but these are generally mild to moderate in severity and do not prevent continuation of the treatment [16, 17]. There is an increased risk of infections with FcRn inhibitors due to the reduction in IgG antibodies, which help to fight infection. Frequently reported infections include respiratory and urinary tract infections. Other common side effects are myalgia (muscle aches) and headache [19, 20, 25]. Contraindications to FcRn inhibitor use are the presence of a systemic infection (infection that has spread into the bloodstream and throughout the body), given the potential of the FcRn inhibitor treatment to worsen the infection. Live or live‐attenuated (a weakened form of the virus/bacteria) vaccines should also be avoided during treatment. Other important treatment considerations include females who are pregnant or breastfeeding. There are currently no safety data on pregnancy, and there is a theoretical risk that FcRn inhibitors can be transported across the placenta to the foetus [19, 20, 25]. The manufacturers therefore advise only considering the use of FcRn inhibitors in pregnancy if the benefits outweigh the risks. It is unknown if FcRn inhibitors are secreted into human milk, thus treatment of women who are breastfeeding should also only be considered if the expected benefit outweighs the risk [19, 20, 25].

Why it is important to do this review

In recent years there has been great progress in the development of targeted immunotherapies for the treatment of MG. Indeed, since 2021, two FcRn inhibitors have been approved in the USA and one in the European Union for use in generalised MG. Other immunotherapy targets in MG include the complement system, with three novel complement inhibitors approved in the USA and two approved in the European Union since 2017 [17]. Despite this rapid development of new therapies, many aspects of treatment with FcRn inhibitors remain unclear [12]. We do not know which participant subgroups benefit most from treatment, and the duration and dosing of these novel agents is unclear. This systematic review will aid our understanding of how FcRn inhibitors are best used in the treatment of MG that is not in crisis.

Objectives

To evaluate the benefits and harms of FcRn inhibitors for the maintenance treatment of myasthenia gravis in adult participants compared with control treatment (placebo, standard‐of‐care therapy, an alternative FcRn inhibitor, or an alternative immunomodulatory therapy).

• We will evaluate the efficacy of the treatment by the effect on disease severity and functional impairment, as assessed using a measurement tool validated for use in myasthenia gravis. Where possible, we will assess whether the effects of FcRn inhibitors differ according to different participant subgroups or different treatment regimens, or both.

• These data will be used to inform policymakers on the participant subgroups most likely to benefit from treatment and the most efficacious treatment regimen.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs, cross‐over RCTs, and quasi‐RCTs. In quasi‐RCTs, participants are allocated to treatment groups using an approach that is systematic but not truly random. Examples of quasi‐randomisation include group allocation based on date of birth, medical record number, or the order in which participants were recruited. An example of a non‐randomised trial would be where participants choose to which group they are assigned, or where researchers choose for them. We will exclude studies that are not randomised or quasi‐randomised. We will also exclude cluster‐randomised trials, as the unit of analysis for this review is the individual participant. We will include cross‐over design studies as long as there was random sequence allocation to the treatment group, and a wash‐out period of at least four weeks prior to the randomisation time frame. We chose a wash‐out period of four weeks as the half‐life of efgartigimod is three to five days, and the clinical elimination of a drug from the body is considered to require five half‐lives [19, 20].

We will include both published data (e.g. full‐text papers and abstracts) and unpublished data (e.g. clinical trial registry data, or data obtained directly from researchers). We will include studies that treated adult participants (aged 18 years and older). We will not use any language restrictions.

Types of participants

We will include participants with MG that fulfil all the following eligibility criteria.

• Disease severity: we will include any classification of disease severity, as per the Myasthenia Gravis Foundation of America (MGFA) clinical system. We will perform subgroup analyses according to disease severity if data are available.

• Antibody status: we will include participants who test positive for AChR, MuSK, or LRP4 autoantibodies, and participants who have seronegative disease. Where possible, we will perform subgroup analyses by antibody status.

• Time of onset: we will include participants with early‐ or late‐onset disease. Where possible, we will perform subgroup analyses by time of onset (early versus late).

• Localisation of disease: we will include participants with ocular or generalised disease. We will perform subgroup analyses according to disease localisation if data are available.

• Thymoma status: we will include participants with thymoma‐associated disease and those with non‐thyomomatous disease. Where possible, we will perform subgroup analyses by thymoma status.

• Previous treatments: we will include participants with MG who have received any previous treatment other than an FcRn inhibitor. We will perform subgroup analyses by previous treatment if data are available.

• Disease duration: we will include participants with any disease duration. Where possible, we will perform subgroup analyses by disease duration.

We will exclude participants that fulfil one or more of the following exclusion criteria.

• Age under 18 years: we will exclude participants with juvenile‐onset MG. Juvenile MG is exceedingly rare, and the disease course is different to adult MG. Additionally, the previous medical management is likely to have been different to adult MG. Thus, the response of participants with juvenile‐onset MG to FcRn inhibitors is likely to differ from participants with adult‐onset MG.

• Previous treatment with an FcRn inhibitor: we will exclude participants who have been previously treated with an FcRn inhibitor.

For identified studies that have only a subset of eligible participants, we will attempt to obtain individual participant data. If this is not possible, then we will include the study if over half of the participants meet the review eligibility criteria.

Types of interventions

We will include studies that investigate the use of any FcRn inhibitor, via any administration method, any dosing regimen, and any treatment duration.

Comparisons (considered individually) will include:

• placebo; or

• standard‐of‐care therapy; or

• an alternative FcRn inhibitor; or

• an alternative immunomodulatory therapy.

We will include studies that involve the co‐administration of other treatments (e.g. steroids, immunosuppressive agents) if both the intervention and control groups received the same co‐administered therapy.

Outcome measures

The outcomes of interest for this review are detailed below; however, evaluating the below outcomes will not be an inclusion criterion for the review.

We will include studies that report follow up at any duration. FcRn inhibitors appear to have a rapid onset of activity within the first four weeks of treatment, with clinical effects persisting for weeks to months afterwards [41]. Given the variable duration of clinical studies, we will subdivide the trials into the following groups according to follow‐up time for analysis; short term (0 to 2 months), medium term (2 to 9 months) and long term (> 9 months). We will consider all outcome data at all follow‐up intervals for inclusion in the analysis. We will use the last time point available within each time frame.

• We will define the short term as 0 to 2 months, as this therapy is marketed as an 'add‐on' treatment for MG, rather than a rescue therapy. In preliminary studies, there is a four‐week treatment period followed by a gap of roughly four weeks, and so the treatment cycle is two months. Following the four‐week treatment period with efgartigimod, preliminary studies showed that trough IgG levels were achieved at approximately 30 days, before returning to baseline by 60 days [41]. The levels of AChR autoantibodies followed a similar pattern over a comparable time period. Therefore, this initial period of rapid IgG and AChR autoantibody depletion is where we are likely to see the earliest clinical effects of FcRn inhibitors, which will be assessed as the impact on functional ability.

• We will define the medium term as 2 to 9 months, as we wish to assess the impact of FcRn treatment on relapse rates and steroid‐sparing effect. These outcomes are likely to be most clinically meaningful at two to nine months post‐treatment, as prednisolone treatment typically takes four to six weeks to achieve clinical benefit, and is usually given for a minimum of two to three months before weaning is considered [11], with an aim to wean over the subsequent four to six months.

• We will define the long term as > 9 months, as this is the earliest time point at which a patient will typically be established on a stable maintenance immunosuppressive regimen, with an initial three months of steroid treatment followed by approximately six months of immunosuppressive therapy before clinical effect is evident [42]. This time point should therefore reflect the utility of FcRn inhibitors as a long‐term maintenance treatment.

Critical outcomes

The critical outcome for this review will be improvement in functional ability or severity of symptoms with FcRn inhibitor treatment compared with control in the short term (0 to 2 months). Functional ability in MG can be measured using a variety of different scales. We will include any of the following functional scales as measures of the critical outcome.

• Myasthenia Gravis Activities of Daily Living (MG‐ADL) score: this scoring system focuses on limitations of daily functioning due to MG. The MG‐ADL will be measured and analysed as continuous data by mean change in score from baseline.

• Quantitative Myasthenia Gravis (QMG) score: the QMG includes a wide range of muscle strength measures, and is the most widely used validated measure in clinical trials in MG. The QMG will be measured and analysed as continuous data by mean change in score from baseline.

We will measure and analyse the critical outcomes as continuous data, in terms of mean change in score from baseline.

We will include additional critical outcomes that focus on reduction in the burden of alternative treatments in the medium term (2 to 9 months). If data are available, we will report the following measures independently.

• Steroid‐sparing effect: we will measure and analyse this outcome as a risk ratio of dichotomous data. We will also assess whether an average dose of prednisolone ≤ 10 mg/day is achieved, which is considered a clinically meaningful target. This may require obtaining individual participant data; if this is not possible, we will perform a narrative synthesis.

• Relapse requiring rescue therapy (including IVIg and plasma exchange): we will compare the rate of requirement for rescue therapy to treat worsening MG, measured and analysed as a rate ratio.

To assess the safety of treatment, we will also consider serious adverse events (SAEs; those that are sentinel events, i.e. fatal, life‐threatening, or that result in prolonged hospitalisation) as a critical outcome. We will assess SAEs by the proportion of participants experiencing any SAE in the intervention group compared with the control group at any time during treatment. We will analyse the data as a risk ratio.

Important outcomes

• Improvement in functional ability or severity of symptoms with treatment (as described in Critical outcomes) in the medium term (2 to 9 months) and long term (> 9 months). In the case of sufficient data, we will also analyse the data dichotomously, to assess whether a significant improvement is seen at the short‐, medium‐, and long‐term time points. This will allow us to evaluate the proportion of responders, as well as the degree of response.

• A clinically significant improvement in MG‐ADL score: a clinical improvement is indicated by a 2‐point improvement in score from baseline to post‐FcRn inhibitor treatment [43].

• A clinically significant improvement in QMG score: a clinically significant improvement is shown by a ≥ 2‐point reduction in the mean score between baseline and post‐FcRn inhibitor treatment in mild‐to‐moderate disease (QMG 0 to 16), or a ≥ 3‐point reduction for severe MG (QMG > 16) [44].

• Myasthenia Gravis Composite (MGC) score: this score combines clinical examination with patient‐reported measures. We will measure and analyse this outcome as continuous data, by mean change in score from baseline. We will assess this outcome in the short term (0 to 2 months), medium term (2 to 9 months), and long term (> 9 months).

• A clinically significant improvement in 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‐FcRn inhibitor treatment [45]. We will assess this outcome in the short term (0 to 2 months), medium term (2 to 9 months), and long term (> 9 months). We will not include other measures of functional ability aside from the MG‐ADL, QMG, and MGC.

• Reduction in burden of alternative treatment (as described in Critical outcomes) in the short term (0 to 2 months) and long term (> 9 months).

• Quality of life, assessed by a change in the Myasthenia Gravis Quality of Life 15 (MG‐QoL‐15) score. We will measure this outcome as a change in score from baseline to the end of the follow‐up period. We will exclude other measures of quality of life.

• Hospital admissions, as a comparison of the rate of hospitalisation pre‐ and post‐treatment, will be evaluated between treatment groups and analysed as a risk ratio.

• Adverse effects (AEs): comparison of the proportion of participants experiencing any adverse effects between treatment groups at any time after the introduction of treatment. We will collect type of AE, timing in relation to FcRn inhibitor treatment, and potential causality if this information is available. AEs will be analysed as risk ratios at any time after the introduction of treatment, and categorised as follows:

  • any AE;

  • treatment (FcRn inhibitor, placebo, standard‐of‐care therapy, or other immunomodulatory drug)‐related adverse events; and

  • AEs that lead to discontinuation of treatment.

• Antibody titre, assessed by the change in titre from baseline to the end of the follow‐up period.

• IgG levels, assessed by the change in titre from baseline to the end of the treatment period.

We will only use the outcome methods specified above in the review.

Search methods for identification of studies

Electronic searches

We will perform a literature search of the following databases:

• Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library;

• MEDLINE (1946 to present);

• Embase (1974 to present).

We will search all databases from their inception to the present day. We will not use any language restrictions in the searches. A draft search strategy is provided in Supplementary material 1. The Information Specialist (KS) will design and quality‐check the search strategy, help translate the search strategy to other databases, and perform the searches. If the search yield is very high, we will consider using the Cochrane‐validated RCT search filters to achieve a more precise search.

We will also search the following clinical trials registries to identify ongoing trials using FcRn inhibitors:

• Clinicaltrials.gov (www.clinicaltrials.gov);

• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/clinical‐trials‐registry‐platform).

Searching other resources

We will review the reference lists of all included primary studies to identify any additional studies that were not identified during the literature search. Where required, we will contact trial investigators for information on any ongoing or unpublished trial data.

We will search for any post‐publication amendments published on included or eligible studies. Post‐publication amendments include expressions of concern, errata, corrigenda, and retractions.

Data collection and analysis

We will summarise the data using the standard methodologies as outlined in the Cochrane Handbook for Systematic Reviews of Interventions [46].

Selection of studies

Two review authors (from LMW, RYSK, KCD) will independently review the title and abstracts of all identified studies using Covidence [47], labelling each study as either 'retrieve' (appears suitable for inclusion or not clear) or 'do not retrieve' (clearly unsuitable for inclusion). A rationale for the inclusion or exclusion of the study literature will be documented. The completed lists will then be compared, with any disagreements between review authors resolved through discussion or the involvement of a third review author (JBL, JSp, or JSu). We will retrieve the full‐text reports of those studies deemed potentially relevant, and the two review authors (from LMW, RYSK, KCD) will independently review the full texts for inclusion in the review. The rationale for inclusion or exclusion will be documented. Any disagreements between review authors will be resolved by discussion or the involvement of a third review author (JBL, JSp, or JSu).

We will contact the study authors for any missing information required to determine study eligibility as needed.

We will identify and remove any duplicate studies. For each individual study we will collate the separate publications, so that each study, rather than each report, is the unit of interest in the review.

We will record the study selection process in sufficient detail to complete a PRISMA diagram [48] and a 'Characteristics of excluded studies' table.

Data extraction and management

We will use the data extraction tools in Covidence [47] to record the study characteristics and outcome data. One review author (LMW) will collate the following data from one included study as a pilot test for the extraction tool.

• Study design and setting

• Baseline characteristics of participants (e.g. age, sex, ethnicity, disease severity)

• Inclusion and exclusion criteria

• Details of the intervention

• Details of the control

• Outcomes assessed

• Details of any funding contributions

• Conflicts of interest (if any)

A second review author (KCD or RYSK) will review and confirm the included data. Following confirmation of the data extraction process from the pilot, the two review authors will review the remaining studies independently and collect the outcome data. For studies reporting additional outcome data that do not fit our predefined critical or important outcomes, these data will still be collected and described narratively in the 'Characteristics of included studies' table. The two review authors will compare the outcome data retrieved, with any disagreements resolved by discussion or the involvement of a third review author (JBL, JSp, or JSu). One review author (LMW) will transfer the data into RevMan software [49]. A second review author (KCD or RYSK) will then review and confirm the data entry.

For any non‐English language publications, either a translator will directly extract the data from the text, or a review author (LMW) will extract the data from the translated version. A second review author (KCD or RYSK) will check and confirm the numerical data collected.

Risk of bias assessment in included studies

Two review authors (from LMW, RYSK, KCD) will independently assess risk of bias in the included studies using the Cochrane RoB 2 tool, as described in the Cochrane Handbook for Systematic Reviews of Interventions [46]. Any disagreements will be resolved by discussion or the involvement of a third review author (JBL, JSp, or JSu).

We will assess risk of bias across the following domains, as per the RoB 2 tool [50].

• Bias arising from the randomisation process

• Bias due to deviations from intended interventions

• Bias due to missing outcome data

• Bias in measurement of the outcome

• Bias in selection of the reported result

We will use the RoB 2 Excel tool (www.riskofbias.info/welcome/rob‐2‐0‐tool/current‐version‐of‐rob‐2) to implement RoB 2. We will grade each potential source of bias as 'low risk of bias', 'some concerns', or 'high risk of bias'. We will create a risk of bias table to document the justification for each grading. We will include quotes or other information from the study literature to support the justification as needed. We will assess the risk of bias for each of the five domains for each included study. We will contact the study authors for any missing information required to make a risk of bias judgement as needed. If the authors are unable to provide sufficient information, we will grade the potential source of bias as some concerns.

To assess the risk of selective outcome reporting, we will attempt to find the study protocol for each of the included studies. We will use the Outcome Reporting Bias in Trials (ORBIT) tool as a framework for this assessment [51].

We will detail any bias related to unpublished data or data provided directly from trial investigators in the risk of bias table.

For each of the critical outcomes (listed below and detailed in Critical outcomes), we will assess the risk of bias for all studies that contribute data for the outcome. We will evaluate the risk of bias within and across studies for each outcome. We will describe the bias assessments and outcome in the risk of bias table.

• Change in MG‐ADL score in the short term (0 to 2 months).

• Change in QMG score in the short term (0 to 2 months).

• Steroid‐sparing effect (whether an average dose of prednisolone ≤ 10 mg/day was achieved) in the medium term (2 to 9 months).

• Relapse that required rescue therapy (including IVIg and plasma exchange) rate in the medium term (2 to 9 months).

• SAEs, assessed by the proportion of participants experiencing any SAE in the intervention group compared with the control group at any time during the treatment period.

For all outcomes assessed using RoB 2, we will use the intention‐to‐treat (ITT) population to assess the effect of assignment to the interventions at baseline, regardless of whether the interventions were received as intended.

To assess the risk of bias in cross‐over trials, we will follow the guidance outlined in the Cochrane Handbook for Systematic Reviews of Interventions [46]. We will use the variant available in RoB 2 that allows for two intervention periods. As described in Types of studies, we will only include cross‐over trials that have a wash‐out period of at least four weeks in order to minimise the carry‐over effect. If unequal numbers of participants are randomised to the different intervention sequences, we will include period effects in the RoB 2 analysis to avoid randomisation bias.

We will establish an overall risk of bias judgement following the guidance in the Cochrane Handbook for Systematic Reviews of Interventions [46]. In short, if all domains are judged to have a low risk of bias, the overall risk of bias will be judged as low. If one or more domains raise some concerns, but none are at high risk of bias, the overall risk of bias will be judged as some concerns. If one or more domains are at high risk of bias, or if there are some concerns for multiple domains such that our confidence in the result is substantially lowered, the overall risk of bias will be judged as high.

We will conduct the systematic review in accordance with this protocol. We will document any differences between the full review paper and this protocol in detail in the Methods section of the full review paper.

If any review authors are involved in a relevant RCT, then they will not be involved in the risk of bias assessments for that study.

Measures of treatment effect

We will use the ITT population for all data analyses.

We will analyse dichotomous outcomes (those with one of two potential values, e.g. hospitalisation, disease relapse, death) using the Mantel‐Haenszel risk ratio (RR) with 95% confidence intervals (CI). We will analyse continuous variables (e.g. changes in MG‐ADL, QMC, MGC, or MG‐QoL‐15 scores) as mean difference (MD) with 95% CIs.

For our critical outcome, it is likely that different studies may use different scores to measure the treatment effect (i.e. MG‐ADL, QMG, or MGC). Where possible, we will collate data for each individual scale for analysis, providing the heterogeneity between studies is not so great that this would not provide a clinically meaningful result. We do not anticipate combining the results for different measurement scales into one measurement for the critical outcome.

Unit of analysis issues

The unit of analysis for the review will be the individually randomised participant.

For trials with multiple intervention arms, we will only include the treatment arms relevant to the review question. Where there are multiple treatment groups relevant to the review question, we will compare each intervention group separately with the control group. We will not pool the treatment groups, and we will not split the control arm. If two different intervention groups from the same trial are to be included in the same analysis, we will separate the comparisons into different forest plots, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions, to avoid double‐counting [46].

We will analyse any trials that compare different FcRN inhibitors to each other with no control arm as a separate comparison.

We will pool dose intervention arms for trials that use different doses of the same intervention according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions [46].

If there is a wash‐out period within the study, the time from treatment will restart once the treatment is recommenced. For cross‐over trials, we will use data if there is a wash‐out period of at least four weeks. We will analyse continuous data from a two‐intervention cross‐over trial with a paired t‐test, to evaluate the value of 'measurement on experimental intervention (E)' minus 'measurement on control intervention (C)' separately for each participant, with the effect estimate included using a generic inverse‐variance approach.

Dealing with missing data

For any studies that do not have published data, we will contact the principal investigator of the trial to request these data (as per Critical outcomes; Important outcomes). We will attempt to contact study investigators to confirm any missing study data. If it is not possible to obtain this information, we will evaluate the effect of the missing data on the validity of the analyses in a sensitivity analysis.

Reporting bias assessment

We will assess reporting bias if 10 or more studies are included in the analysis. We will create a funnel plot for the included studies to visually assess for the risk of bias. If there is any asymmetry observed in the funnel plot from visual inspection, we will analyse the asymmetry formally using Egger’s test [50, 52]. It will not be possible to evaluate reporting bias if there are fewer than 10 studies included for an outcome measure.

Synthesis methods

We will use the random‐effects model available in RevMan [49] to synthesise the data, as this is considered to be a more conservative approach. We will perform sensitivity analysis to determine whether a fixed‐effect model makes a difference to the conclusions drawn (see Sensitivity analysis)

If the included studies have sample sizes that are substantially different, we will perform a sensitivity analysis to evaluate the effect of sample size on the results.

We will include studies with an overall low risk of bias in the primary analysis. We will perform sensitivity analyses to demonstrate how our conclusions might be affected if studies with a high risk of bias are included.

Before performing the meta‐analysis, we will explore whether the studies are sufficiently similar for a meaningful analysis, using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions [46].

Comparisons of interest include:

• placebo; or

• no treatment; or

• an alternative FcRn inhibitor; or

• an alternative immunomodulatory therapy.

For studies that report more than one intervention, we will analyse each comparison with control treatment separately, unless we are able to combine the data. Furthermore, we will also collate and report different comparators (e.g. placebo treatment, standard‐of‐care therapy, alternative FcRn inhibitor, or alternative immunomodulatory therapy) separately, rather than combining all comparators.

If meta‐analysis of effect estimates is not possible, we will summarise the effect estimates using the Synthesis Without Meta‐analysis (SWiM) reporting guideline [53].

Investigation of heterogeneity and subgroup analysis

We will investigate heterogeneity between studies using the I² and Chi² statistics. We will interpret the I² value using the rough guide for interpretation of results detailed in the Cochrane Handbook for Systematic Reviews of Interventions [46]:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

However, the values are not absolute cut‐offs, and each I² result will be considered individually in 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).

We will report any analyses with substantial or considerable heterogeneity. We will investigate the causes of the heterogeneity using subgroup analysis (see Investigation of heterogeneity and subgroup analysis). We will consider the I² and Chi² results alongside the size and direction of the observed effect.

We will assess methodological heterogeneity by comparing study designs. We will assess clinical heterogeneity by reviewing participant characteristics between studies.

We will perform the following subgroup analyses where possible for the critical outcomes.

• Disease subtypes (as pathophysiology may vary):

  • early‐ (age < 45 years) versus late‐onset MG (age > 45 years), as defined previously [5];

  • ocular versus generalised MG;

  • AChR antibody‐positive versus MuSK antibody‐positive versus LRP4 antibody‐positive versus seronegative MG.

• Disease duration (as earlier treatment may be more effective): we will compare participants according to disease onset within the last two years versus over two years ago.

• FcRn inhibitor (as differing therapies may have differing efficacies): we will compare participants according to FcRn inhibitor received (e.g. efgartigimod, rozanolixizumab, nipocalimab, or batoclimab).

We will perform the subgroup comparisons using the formal test for subgroup differences in RevMan [49].

Equity‐related assessment

We will not investigate health inequity in this review. While certain data related to health inequity may be collated within the included studies, a detailed examination of health inequity is beyond the scope of this review.

Sensitivity analysis

We will complete sensitivity analyses to investigate whether studies with a high overall risk of bias (defined as high risk in one or more domains) and studies with missing data should be excluded from the overall analysis. We will detail the results of the sensitivity analyses in a summary table.

We will compare our random‐effects model with a fixed‐effect model to investigate the effect of study size on the outcomes of interest. The fixed‐effect model will weigh studies according to the population size (with larger trials carrying a greater weight for the analysis). We will also compare the use of RR to odds ratio, to investigate if this would have changed the effect.

Certainty of the evidence assessment

We will detail the results of the critical outcomes in a summary of findings table. We will create the table using GRADEpro GDT [54]. The overall risk of bias assessment (as detailed in Risk of bias assessment in included studies) will be used to assess the certainty of the evidence.

We will focus on the comparison 'any FcRn inhibitor versus placebo' for the outcomes as specified in the Critical outcomes section, as follows.

• Change in MG‐ADL score in the short term (0 to 2 months).

• Change in QMG score in the short term (0 to 2 months).

• Steroid‐sparing effect (whether an average dose of prednisolone ≤ 10 mg/day was achieved) in the medium term (2 to 9 months).

• Relapse that required rescue therapy (including IVIg and plasma exchange) rate in the medium term (2 to 9 months).

• SAEs, as assessed by the proportion of participants experiencing any SAE in the intervention group compared with the control group at any time during the treatment period.

If a 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.

We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to independently evaluate the certainty of the evidence for the critical and important outcomes [55], in addition to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions [46]. Two review authors (from LMW, KCD, or RYSK) will independently assess the certainty of the evidence. Any disagreements will be resolved by discussion or the involvement of a third review author (JBL, JSp, or JSu) if required. We will record the rationale for each judgement in the risk of bias section of the 'Characteristics of included studies' table. If any authors are involved in a relevant RCT, then they will not be involved in the GRADE assessment for that study.

Consumer involvement

One of the review authors is an experienced patient‐author. They will be involved from the beginning of conceptualisation of the article throughout the review process. Their opinion will be sought at each stage of protocol development. In particular, they will help to identify which outcomes and time points are of the greatest importance to patients.

Supporting Information

Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016097.

Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

Supplementary material 1 Search strategies

New

Additional information

Contributions of authors

KCD conceived the idea for the review and contributed to the design and co‐ordination of the protocol.

LMW wrote the protocol and contributed to the design and co‐ordination of the protocol.

KS provided methodological input.

All authors (LMW, FJC, A‐MF, RYSK, JBL, JSp, KS, JSu, KCD) reviewed the protocol, contributed to manuscript revisions, and approved the final version.

Declarations of interest

LMW: I do not have any interests to disclose at this time.

FJC: I do not have any interests to disclose at this time.

A‐MF: I do not have any interests to disclose at this time.

RYSK: Received a travel and accommodation grant from CSL Behring for the Peripheral Nerve Society meeting, Baltimore, July 2018.

JBL: Declares personal payments from Biogen (webinar host November 2021, booked but not attended), Sanofi (travel and speakers fees for STEPS Forward meeting 2022; consultancy in collaboration with VOLV 2021; and speaker fees February 2020), Hoffman‐La Roche (participation in SMA HCRU Delphi Panel 2024; advisory meeting 2023, advisory board 2022), and Roche (advisory board 2020; writing support for a business case), Neuromuscular Study Group (executive committee member (no fiduciary interest)), Myositis UK (attendance at Global Conference on Myositis), British Myology Society (Vice chair (no fiduciary interest)), British Medical Association (production and update of an article for BMJ Best Practice).

JSp: Declares travel support, speakers fees, and collegium work for Argenx, and travel support and expert panel work for UCB.

KS: I do not have any interests to disclose at this time.

JSu: I do not have any interests to disclose at this time.

KCD: I do not have any interests to disclose at this time.

Sources of support

Internal sources

• No internal funding support, UK

  No internal funding support

External sources

• National Institute for Health Research, Queen Square Centre for Neuromuscular Diseases, UK, Other

  This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Neuromuscular Disease Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health. Cochrane Neuromuscular is also supported by the Queen Square Centre for Neuromuscular Diseases.

Registration and protocol

Cochrane approved the proposal for this review in December 2023.

Data, code and other materials

As part of the published Cochrane Review, the following is made available for download for users of the Cochrane Library: Full search strategies for each database; full citations of each unique report for all studies included, ongoing or waiting classification, or excluded at the full text screen, in the final review; study data, including study information, study arms, and study results or test data; consensus risk of bias assessments; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows]. Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, RevMan, using the inbuilt computation methods. The following scripts and artefacts were used to generate analyses outside of RevMan: [list each including the public archive and citation]. Template data extraction forms from [Covidence, Excel, etc.] are available [from the authors on reasonable request.

Data sharing not applicable to this article as it is a protocol, so no datasets were generated or analysed.

Notes

Published notes in RevMan are for editor use only. Authors should leave this section blank.