New and Emerging Biological Therapies for Myasthenia Gravis: A Focussed Review for Clinical Decision-Making.

Key Points

Standard treatment of myasthenia gravis does not achieve a satisfactory clinical improvement and stability in 30–50% of patients. Therefore, more effective and safe drugs are needed. After decades of therapeutic stagnation, a new era has begun with the regulatory approval of complement inhibitors and FcRn inhibitors as add-on therapy. This enables a shift from pure broad-spectrum immunosuppressants to a combination with targeted immunotherapies, which should be used in patients with high disease activity, even in the early course of the disease. Additionally, several new biologicals, including B- and T-cell targeting and cell-based strategies such as CAR-T cell therapies, are being investigated. For clinical decision-making, and to achieve the best possible treatment for the individual patient, further insights from real-world data and comparative studies as well as predictive biomarkers are needed to enable tailored and individualised therapy, to obtain guidance on discontinuation or switching between drugs and to provide information on possible synergistic or antagonistic effects.

Introduction

Myasthenia gravis (MG) is a rare, chronic neurological disorder characterised by specific autoantibodies directed against the neuromuscular junction. Symptoms present as fluctuating and exertion-induced muscle weakness and can include potentially life-threatening myasthenic crises. MG is a chronic condition that can be improved through therapies, but to date, not cured. Because of its well understood pathophysiology, MG serves as an exemplary disease for antibody-driven disorders in general and as a proof-of-principle condition for new therapeutic substances.

MG can be classified according to the detectable autoantibodies (ab), age at onset, thymic pathology, clinical manifestation (ocular versus generalised) and disease severity. More recently, the stratification into mild-to-moderate versus high disease activity (including treatment-refractory status) has gained importance, as treatment strategies are being adapted in the wake of new therapeutic options.

After decades of therapeutic stagnation and lack of evidence from phase 3 trials, a new era has begun with the regulatory approval of several monoclonal antibodies (namely complement inhibitors and neonatal fragment crystallisable receptor [FcRn] inhibitors) as add-on treatment regimens for generalised MG (gMG). Nevertheless, the burden of disease for those affected remains high and the need for more specific and more effective drugs remains relevant.

A Short Look into History—The Path from Lying in Bed to Monoclonal Antibodies

Historically, from its first description as myasthenia gravis pseudoparalytica in 1895 by Friedrich Jolly [ 1 ], ‘treatment’ consisted of lying in bed for most of the day, as symptoms are partially improved after rest. Around 1900, it was assumed that the mortality of severe cases was almost 100%. From the 1920s onwards, the development of modern intensive care medicine with the possibilities of mechanical ventilation (specifically the ‘iron lung’, originally developed for people suffering from polio) and the development of antibiotics significantly increased survival chances for patients with a myasthenic crisis [ 2 ]. In 1934 Mary Broadfoot Walker established the concept of acetylcholine-esterase inhibition as symptomatic treatment [ 3 ]. In the early 1960s, John Simpson recognised that MG is an autoimmune disease [ 4 ], and in the mid-1970s, it became clear that the disease is mediated by autoantibodies. These realisations led to two important milestones in the treatment of gMG: the introduction of plasmapheresis as a therapeutic procedure and the use of high-dose oral steroid treatment and subsequently steroid-sparing immunosuppressants such as azathioprine and ciclosporine [ 2 , 5 – 7 ]. Mortality decreased substantially, but the proportion of patients with long-term remission remained low [ 2 ].

The first monoclonal antibody that was used to treat MG was the chimeric anti-CD20-antibody rituximab. However, due to conflicting evidence [ 8 – 11 ] it remained a treatment for few patients and is mainly used for refractory cases and muscle-specific tyrosine kinase (MuSK)-ab positive MG. Finally, a new era began in the treatment of MG with the regulatory approval of the first complement inhibitor eculizumab in 2017 [ 12 ].

New Drugs and Improved Evidence: the Era of Randomised Controlled Trials in Myasthenia Gravis

In recent years, the MG landscape has been influenced by an ever-increasing number of randomised controlled trials for numerous new therapies, mainly monoclonal antibodies. Early on, in 2000, the MG Foundation of America (MGFA) Taskforce on Clinical Research Standards proposed a set of guidelines to improve recording and reporting of clinical trials in MG, including standardisation of clinical outcome measures [ 13 ]. The guidelines were updated in 2012 [ 14 ]. In recent clinical trials, usually a combination of an examiner-determined physical examination scores, such as the quantitative myasthenia gravis (QMG) [ 15 ] score or the myasthenia gravis composite (MGC) [ 16 ], and a patient-reported outcome measure, such as myasthenia gravis activities of daily living (MG-ADL) [ 17 ] and myasthenia gravis quality of life (MG-QoL15 or MG-QoL15r) [ 18 , 19 ] score, are being employed. For these outcome measures, a 3-point change in QMG [ 20 ], a 3-point change in MGC [ 14 ] and a 2-point change in MG-ADL [ 21 ] are regarded as a clinically meaningful improvement. Of note, most of the recent phase 3 trials utilised the patient-reported outcome measure MG-ADL as the primary endpoint. However, in most cases, the regulatory approval of new drugs for MG was based on response and improvement in the more objective secondary measure, for example, QMG.

While the clinically meaningful improvement in standardised scores is an important measure to evaluate new treatment options, the treatment goal for an individual patient should either be minimal symptom expression or remission status. The score that correlates best with minimal symptom expression is the Patient Acceptable Symptom State (PASS) [ 22 , 23 ].

The standardisation of clinical outcome measures has led to improved evidence for treatment decisions but also influenced how disease course is being monitored. Therefore, clinical outcome measures used in MG trials not only play an important role in the research setting, but also in routine clinical and telemedical care to assess disease severity and activity and ultimately to guide therapy. A recent European expert consensus statement [ 24 ] recommends the consistent use of the MG-ADL across clinical settings, followed by a patient-reported outcome measure that determines patient satisfaction with disease status (e.g. PASS). In a second step, the use of the QMG and/or MG-QoL is recommended when the MG-ADL indicates disease worsening.

Aim of the Review

In this focussed review, we provide an overview of the new biologicals and discuss their use in the context of standard treatment and medical need in MG care. To this end, we present the available trial data for the approved biologicals, as well as those expected to come to market soon, and discuss the emerging real-world data for already approved drugs. Finally, we propose a pathway for clinical decision-making that is based on MG classification, the available data and patient preference.

Diagnosis and Classification of Myasthenia Gravis

Diagnosis of MG

The diagnosis of the disease is primarily based on the typical clinical appearance of the disease with exercise-induced muscle weakness, which can at least partially disappear after rest. This is often accompanied by a time-of-day dependency with more severe symptoms in the evening than in the morning. Most patients with MG present at first with ocular symptoms only. However, approximately 80% of cases subsequently develop gMG [ 2 ]. The disease can be confirmed by detecting the above-mentioned specific antibodies: approximately 75–85% of cases have detectable acetylcholinreceptor (AChR)-ab, 5–8% have detectable MuSK-ab and 1–3% have low-density lipoprotein receptor-related protein 4 (LRP4)-ab. However, approximately 5–15% of cases remain seronegative [ 25 – 28 ]. Serological testing should be accompanied by electrophysiological examinations: repetitive nerve stimulation (showing a decrement) detects gMG with around 75% sensitivity (ranging from 32% to 98% sensitivity) and single fibre electromyography (showing prolonged jitter or blocking of transmission) with around 75–98% of sensitivity but much lower specificity (≤ 70%) [ 29 , 30 ]. Further, pharmacological testing can be performed with edrophonium, a reversible acetylcholinesterase inhibitor with rapid but short-lasting action. Similar to symptomatic treatment with longer lasting acetylcholinesterase inhibitors (such as pyridostigmine), it increases the concentration of acetylcholine in the synaptic cleft, thus improving neuromuscular transmission and reducing the symptoms.

In unclear diagnostic situations with seemingly clear clinical picture and high disease activity, but seronegative and electrophysiology negative status, further specialised procedures might be employed, such as intercostal muscle biopsy and histopathological examination of the neuromuscular junction [ 31 ].

As part of the initial diagnosis of myasthenia gravis, thymus gland imaging must always be carried out to clarify the presence of a thymoma [ 7 ].

Classification of MG

MG is a heterogenous disease, and some have gone this far as to say that MG is merely an umbrella term encompassing several distinct entities. Clinical subtypes exist on the basis of age at onset, autoantibody profile, clinical manifestation, gender distribution and thymic pathology. Disease severity is assessed with MGFA class (I–V) and has recently been extended with stratification into mild-to-moderate versus high disease activity (including treatment-refractory status) (Fig. 1 ). While most of the classification criteria remain individually unchanged during the course of the disease, it is in the nature of this chronic autoimmune disease that disease activity can change spontaneously as well as in response to therapy. Fig. 1 Classification of MG. Overview of the different subtypes of MG: approximately 80–85% have AChR-ab. AChR-ab+ MG is classified according to age at onset into EOMG, LOMG and if associated with a thymoma, as TAMG. EOMG with female predominance, LOMG with male predominance. TAMG is evenly distributed between sexes. Approximately 1–3% have LRP4-ab; main age at onset of this subtype is 40–70 years. AChR- and LRP4-ab are of the immunoglobulin (Ig)G1–3 subtype. Approximately 5–15% remain seronegative; main age at onset is 30–60 years. Approximately 5–8% have MuSK-ab, which are of the IgG4 subtype and cause a distinct clinical phenotype. Main age at onset for MuSK-ab+ MG is between 20 and 60 years. jMG can be defined on the basis of the age-related classification, but should not be considered as a homogenous sub-group of MG. For example, jMG differs in some aspects from adult MG, for example, patients with jMG are more likely to be seronegative. According to the clinical manifestation, MG is categorised into ocular and generalised MG. Approximately 80% of patients with ocular presentation show a generalisation within the first 2 years after diagnosis. Generalised MG can be stratified according to MGFA IIa–V and according to disease activity into mild/moderate or high disease activity. In recent classifications, high disease activity encompasses treatment-refractory status. AChR-ab acetylcholine-receptor-antibody, EOMG early onset myasthenia gravis, IgG immunoglobulin G, jMG juvenile MG, LOMG late onset myasthenia gravis, LRP4-ab low-density lipoprotein receptor-related protein 4 antibody, MG myasthenia gravis, MGFA myasthenia gravis Foundation of America Classification, MuSK-ab muscle-specific tyrosine kinase antibody, TAMG thymoma-associated myasthenia gravis. All figures in this review have been created with biorender.com.

Appropriate recognition of these clinical subtypes is highly important because treatment strategies vary accordingly, for example, indication for thymectomy and biologicals depends on the subtype. We here give a focussed overview of the different subtypes and their (potential) consequences for treatment choices.

Firstly, the detected antibody determines different treatment strategies: AChR-ab and LRP4-ab belong to the IgG1 (–3) subtype and can therefore activate the complement system. In these subtypes, complement inhibition is a feasible treatment strategy. MuSK-ab in contrast belong to the IgG4 subtype and do not activate the complement system. This might in part explain the clinically distinct entity of MuSK-ab positive (MuSK-ab+) gMG with predominant weakness in bulbar and respiratory muscles.

AChR-ab positive (AChR-ab+) gMG is classified according to age at onset into early onset MG (onset < 50 years; EOMG) and late onset MG (onset > 50 years; LOMG). Together with the thymic pathology (thymoma-associated MG; TAMG versus non-thymoma-associated MG with either normal thymus, thymus hyperplasia or thymitis) age at onset is an important factor for prognosis of disease course and indication of thymectomy. If the disease starts in childhood or puberty, it is classified as juvenile MG (onset < 18 years; jMG). jMG has many features distinct from MG in adults, and there are sub-classifications for jMG which are discussed elsewhere [ 32 ].

The group of seronegative patients probably consists of different sub-groups and some patients might have still unknown antibodies. A study in 13 seronegative patients showing complement deposition at the neuromuscular junction indicates that this group might benefit at least in part from complement inhibition as treatment strategy [ 31 ].

In Japan these categories are summarised in the o-gELTMuN classification: first, patients with MG are separated into o cular and g eneralised forms. Then, generalised MG is divided into the following five subsets: AChR-ab+ e arly-onset MG, AChR-ab+ l ate-onset MG, AChR-ab+ t hymoma-associated MG, Mu SK-ab positive (MuSK-ab+) MG and sero n egative MG [ 33 ]. While both the o-gELTMuN and the MGFA classification differentiate between ocular and generalised myasthenia, the MGFA classification focusses on disease severity, while the o-gELTMuN classification focusses on antibody-status and sub-groups within MG that necessitate different treatment approaches.

As in most autoimmune diseases, more women are affected by MG than men. AChR-ab+ EOMG, LRP4-ab+, MuSK-ab+ and seronegative MG have a clear female predominance, while AChR-ab+ LOMG has a male predominance. Thymus hyperplasia is more often found in female patients with MG while gender distribution in TAMG is more or less equal [ 25 , 34 ]. Studies indicating a higher disease burden and lower quality of life in women with MG indicate that female gender might be an independent risk factor for high-disease activity and/or treatment-refractory status [ 26 , 35 – 37 ].

Finally, disease course (clinical manifestation as ocular or generalised MG and disease severity according to MGFA class) and disease activity (mild-to-moderate versus high disease activity including treatment-refractory status) influence the recommended first-line therapy and the use of new biologicals.

Defining the Term ‘Treatment-Refractory’ MG

After the regulatory approval of eculizumab for ‘treatment-refractory’ gMG in the EU, a discussion was started as to how the term ‘treatment-refractory’ should be defined. Operational definitions were adopted and the following five criteria mainly emerged: failure to respond adequately to conventional treatment, inability to reduce immunosuppressive therapy without clinical relapse or need for ongoing rescue therapy (e.g. intravenous immunoglobulins [IVIg] and/or plasma exchange [PLEX] or immunoadsorption [IA]), severe or intolerable adverse effects from immunosuppressive or symptomatic therapy, comorbid conditions restricting use of conventional therapies and frequent myasthenic crises even while on immunosuppressive and symptomatic therapy [ 38 , 39 ]. In most recent classifications, the term ‘treatment-refractory’ is being encompassed within the group of high diseases activity [ 40 ].

Standard Treatment of Myasthenia Gravis

Standard treatment of MG consists of symptomatic treatment with acetylcholine-esterase-inhibitors and disease-modifying treatment with steroids and steroid-sparing immunosuppressants for long-term management [ 41 ]. Patients fulfilling criteria for prognostic importance of thymectomy should undergo thymectomy within the first 2 years after diagnosis. An overview of standard treatment and newly approved agents for MG according to severity of adverse effects (AEs) and latency of clinical improvement is provided in Fig. 2 . Fig. 2 Treatment of MG: latency of clinical improvement and magnitude of adverse effects for different therapies. Overview of standard treatment and newly approved agents for MG according to potential severity of adverse effects (AEs) and latency of clinical improvement. Severity of adverse effects is often dose dependent (especially for steroids) and latencies of clinical improvement should be seen as estimates. AChE-I acetylcholine esterase inhibitors, AZA azathioprine, C5-I complement factor 5 inhibitor, CSA cyclosporin A, FcRn-I neonatal fragment crystallisable receptor inhibitor, GCS glucocorticosteroids, IA immunoadsorption, IVIg intravenous immunoglobulins, MMF mycophenolate mofetil, MTX methotrexate, PLEX plasmapheresis, RTX rituximab, TAC tacrolimus. All figures in this review have been created with biorender.com.

Symptomatic Treatment

Symptomatic treatment with pyridostigmine is part of the initial treatment in most patients with MG. Individual tolerability in terms of dose-dependent side effects varies and pyridostigmine dose should be adjusted on the basis of symptom severity and in a flexible manner. To achieve this, patient education is essential. A reduction of pyridostigmine dose can indicate that the disease has stabilised and should guide the tapering of other therapies [ 41 , 42 ].

Treatment of Exacerbations and Crises

Treatment of exacerbations and crises remain essentially unchanged and is carried out with intravenous immunoglobulins (IVIg) and/or plasma exchange (PLEX) or immunoadsorption (IA). Improvement from IVIg usually starts within a few weeks after and lasts 4–8 weeks. PLEX rapidly lowers antibody levels and removes pro-inflammatory factors contained in the plasma. The effect lasts for about 3 weeks. Because of its rapid onset of efficacy, PLEX is the recommended treatment for life-threatening myasthenic crises. However, in a situation with a severe ongoing infection, IVIg might be the safer approach albeit onset of improvement is slower than with PLEX. Overall efficacy of both strategies is similar. To maintain long-term minimal symptom expression or even pharmacological remission, additional immunosuppressants are usually needed [ 41 ].

Both therapies are also being used as maintenance strategies for patients with refractory MG, but evidence and recommendations for this approach vary. A clear recommendation exists only in Japan, where the guidelines for treatment of MG recommend early fast-acting treatment (EFT)—either IVIg or PLEX often combined with high-dose intravenous methylprednisolone (IVMP)—in patients in whom a reduction of steroid-dosage to 5 mg is otherwise not possible [ 43 , 44 ]. Of note, Japanese guidelines recommend EFT before employment of more targeted biologicals such as C5 or FcRn inhibitors.

Disease-Modifying Treatment

Steroids

Since their introduction into MG therapy in the 1960s, steroids still play an essential role in disease-modifying treatment due to their fast onset of action. Long-term treatment with steroids is limited by relevant systemic side-effects such as, but not limited to, weight gain, diabetes, high blood pressure, cataract and osteoporosis. Therefore, steroid dosage should be tapered as soon as possible below 5 mg and steroid-sparing immunosuppressants should be started early in the disease course [ 40 , 44 ].

Steroid-Sparing Immunosuppressants

Long-term immunosuppressants that are being used for treating MG are azathioprine, cyclosporine A (CSA), methotrexate (MTX), mycophenolate-mofetil (MMF) and tacrolimus. Treatment approaches as to which drug is first or second choice vary between countries due to a lack of comparative studies. However, azathioprine appears to be used most. Clinical effects can be expected to start after 12 months of treatment [ 5 ]. In the long-term, azathioprine is relatively safe and well tolerated. Side effects include liver toxicity, gastrointestinal, haematological, dermatological and infectious events. Rarely, severe bone marrow toxicity occurs. MMF is mostly used as second-line immunosuppressant after azathioprine and clinical effects can be expected after 6–12 months. Recent data suggest very similar efficacy of MMF compared with azathioprine [ 45 ]. The safety profile is similar to azathioprine with one important difference: MMF is teratogenic and should therefore be discontinued several months before planning a pregnancy. CSA is another second-line immunosuppressant with a much faster clinical response which can start as early as after 2 months. The safety profile of CSA includes an elevated risk of nephrotoxicity. Further, hypertension, paraesthesia, gum sensitivity, altered taste, increased hair growth, headache, muscle cramps and diarrhoea have been reported. Tacrolimus is mainly used in Japan and China. It also induces a fast clinical response which can start as early as after 2 months. The safety profile is comparable to CSA. MTX is mostly considered a third-line choice in patients who do not tolerate other immunosuppressants. Clinical response can be expected after 3–6 months [ 41 , 42 ].

In patients with MuSK-ab+ MG, rituximab should be considered earlier in the treatment pathway than for patients with AChR-ab+ MG [ 41 ]. Rituximab is being discussed in detail in Sect. 4 of this review.

Thymectomy

The phase 3 MGTX trial, a randomised, single-blind trial, showed efficacy of thymectomy plus prednisolone (versus prednisolone only) for AChR-ab+ MG patients aged 18 to 65 years. Patients in the thymectomy group showed a reduction of prednisolone dose and an improvement in QMG over the 3-year follow-up period [ 46 ]. Treatment guidelines recommend thymectomy in patients with a thymoma or thymic enlargement on chest imaging. In non-thymoma-associated MG, thymectomy is recommended in patients with a AChR-ab+ gMG who are younger than 65 years and are within the first five (better two) years after diagnosis [ 40 , 41 , 47 ].

Overall, between 50% and 70% of patients with gMG achieve minimal manifestation, pharmacological remission or complete stable remission under standard treatment [ 45 , 48 ]. The use of steroids is limited by significant adverse effects and the use of standard steroid-sparing immunosuppressants as well as thymectomy show a relevant clinical response only after months or years [ 42 , 48 ]. Taken together, this highlights the need for better tolerated, more targeted therapies to treat gMG.

New and Emerging Biological Therapies

MG is considered a prototypic autoimmune disease with a B-cell-mediated T-cell-dependent pathogenesis with known autoantibodies and IgG subtypes in the majority of cases with a multitude of different targeted mode of actions as potential therapeutic strategies. Figure 3 and Table 1 give an overview of all therapeutic agents, their biological target structures and route of administration. Fig. 3 Modern therapeutic agents for myasthenia gravis. Overview of the different modern therapeutics for MG according to their biological targets and including their route of administration: fast acting are complement inhibitors and FcRn inhibitors, while slower action onset is displayed by B- and T-cell targeting, cytokine-targeting biologicals and cell-based therapies. The coloured box behind each therapy indicates the level of evidence and whether regulatory approval exists. AChR acetylcholine receptor, BAFF B-cell activating factor, BAFF-R BAFF-receptor, BCMA B-cell maturation antigen, BCR B-cell receptor, BlyS B-lymphocyte stimulator, BTK Bruton’s tyrosine kinase, C5 complement factor 5, CAR chimeric antigen receptor, FcR fragment crystallisable receptor, FcRn neonatal fragment crystallisable receptor, ICOS inducible T-cell costimulatory, ICOS-L ICOS-ligand, IL6-R interleukin 6 receptor, TCR T-cell receptor. All figures in this review have been created with biorender.com. Table 1 Overview of new and emerging biological therapies in myasthenia gravis Drug Type of drug Target Effect/mechanism Evidence/study in MG Type of MG in study/case Approval for MG B-cell and plasma cell targeting In clinical use (off-label) Rituximab Chimeric mouse/human monoclonal IgG1 ab CD20 Depletion of CD 20 cells Phase 2 study (Beat MG); NCT02110706 ; [ 10 ] AChR and MuSK Off-label-use in AChR-ab+ and MuSK-ab+ gMG MuSK: Class IV evidence (multicentre blinded prospective review; NCT02110706 ; [ 9 ] Only MuSK In clinical use in single cases Obinutuzumab Humanised IgG1κ monoclonal ab CD20 Cell death of CD 20 cells Case report [ 89 ] Case: AChR-ab+ MG + CLL – Ofatumumab Human IgG1 monoclonal ab CD20 Depletion of CD 20 cells Case report [ 90 ] Case: AChR-ab+ – Daratumumab Human monoclonal IgG1κ ab CD38 Reduction of plasma cells, plasmablasts, regulatory T- and NK- cells Case series (1 MG case) [ 93 ] Case: seronegative Off-label-use in single cases Bortezomib Proteasome inhibitor Proteasome Inhibition of plasma cell and long-lived B cell proliferation, depletion of short- and long-lived B-cells Case reports [ 98 , 99 ] Cases: MuSK-ab+; MuSK-ab+ and MM Off-label-use in single cases Phase 2a study terminated due to recruitment difficulties; NCT02102594 [ 100 ] – In trials Inebilizumab Humanised IgGκ monoclonal ab CD19 Depletion of CD 19 cells Phase 3 study ongoing; NCT04524273 AChR and MuSK Belimumab Human monoclonal IgG1λ BAFF/BLyS Reduction of B-cell differentiation and maturation, reduction of CD 20-cells Phase 2 study published with negative results; NCT01480596 [ 109 ] AChR and MuSK Telitacicept (RC18) TACI-Ig fusion protein BAFF/BLyS and APRIL Reduction of mature B-cells Phase 2 study published [ 111 ] NCT04302103 AChR and MuSK Phase 3 trial starting in 2024; NCT06456580 AChR and MuSK Tolebrutinib Small molecule BTK Irreversibly binds and inhibits BTK and modulates B-cell maturation, survival and activation and reduces inflammation Phase 3 trial in MG terminated for strategic reasons; NCT05132569 AChR, MuSK, seronegative Mezagitamab (Tak-079) Human monoclonal IgG1 ab CD 38 Reduction of plasma cells, T and NK cells Phase 2 study completed, negative results posted on NCT; NCT04159805 AChR and MuSK Complement inhibition Regulatory approval Eculizumab Humanised monoclonal IgG 2/4κ ab C5 Inhibition of terminal complement/MAC activation Phase 3 study published; REGAIN trial, [ 12 ] AChR In-label as add-on (USA) and for refractory (EU) AChR-ab+ gMG Ravulizumab Humanised monoclonal IgG 2/4κ ab C5 Inhibition of terminal complement/MAC activation Phase 3 study published; CHAMPION MG trial [ 58 ] AChR In-label (add-on) for AChR-ab+ gMG Zilucoplan Short 35 kDa macrocyclic peptide C5/C5b Inhibition of terminal complement/MAC activation Phase 3 study published; RAISE trial [ 62 ] AChR In-label (add-on) for AChR-ab+ gMG In trials Gefurulimab (ALXN1720) Bispecific VHH antibody C5/human serum albumin Inhibition of terminal complement/MAC activation Phase 3 study ongoing; NCT05556096 AChR – Pozelimab + Cemdisiran Human monoclonal IgG4 P antibody/ siRNA C5/ C5-RNA Inhibition of terminal complement/MAC activation/reduction of hepatic C5 level Phase 3 study ongoing; NCT05070858 AChR and LRP4 – Iptacopan (LNP023) Small molecule Complement factor B Inhibition of alternative complement pathway Phase 3 study ongoing; NCT06517758 AChR – Vemircopan (ALXN2050) Small molecule Complement factor D Inhibition of alternative complement pathway Phase 2 study in MG terminated by sponsor ( NCT05218096 ); reasons unavailable at time of writing AChR – Neonatal Fc-receptor inhibition Regulatory approval Efgartigimod Anti-FcRn-IgG1 Fc fragment FcRn Inhibition of IgG3 > IgG4 autoantibody recycling, reduction of auto ab levels Phase 3 study published; ADAPT [ 73 ] Phase 3 study, comparing SC and IV regimens in MG; completed, not published; NCT04735432 AChR, MuSK, seronegative In-label (add-on) for AChR-ab+ gMG Rozanolixizumab Human anti-FcRn IgG4 ab FcRn Reduction of auto ab levels Phase 3 study published; MycarinGstudy; [ 76 ] AChR and MuSK In-label (add-on) for AChR-ab+ and MuSK-ab+ gMG In trials Batoclimab Humanised IgG1 monoclonal ab FcRn Reduction of auto ab levels Phase 3 study ongoing (USA and Europe), study protocol published [ 81 ], NCT05403541 ; Phase 3 study published (China) [ 79 ], NCT05039190 AChR and MuSK Nipocalimab (M281) Human aglycosylated IgG1 anti-FcRn monoclonal ab FcRn Reduction of auto ab levels Phase 2 study published, Vivacity-MG, NCT03772587 ; [ 82 ] AChR and MuSK Phase 3 study completed, not published; NCT04951622 AChR, MuSK, LRP4, seronegative B- and T-cell targeting Cladribine Purine analogue B and T cells Reduction of B and T cells Pilot open-label study published [ 117 ]; AChR Phase 3 trial ongoing; NCT06463587 AChR, MuSK, LRP4, seronegative T-cell targeting Iscalimab (CFZ533) Monoclonal ab CD40 Non-depleting, blocking of CD40, blocking of primary and recall T-cell-dependent antibody responses Phase 2 trial published; [ 120 ]; NCT02565576 AChR and MuSK Cytokine targeting Satralizumab Humanised IgG2 monoclonal ab IL-6R IL-6R signalling blockade, inhibition of T-cell activation and differentiation Phase 3 study completed, abstract on baseline data available; LUMINESCENCE; NCT04963270 AChR, MuSK, LRP4 Tocilizumab Humanised monoclonal ab IL-6R IL-6R signalling blockade, inhibition of T-cell activation and differentiation Retrospective case series; [ 124 ] 2 prospective, open-label-studies [ 125 , 126 ] AChR AChR Cell-based therapies Autologous hematopoietic stem cell transplantation – – Immune ablation and repopulation 15 cases reported, [ 127 – 132 ] AChR, MuSK, and seronegative Ultima ratio for single cases Phase 1 study terminated; NCT00424489 – Phase 2 ongoing (Fred Hutchinson Cancer Center); NCT00716066 Not MG specific In trials Descartes-08, rCAR T Cells anti-BCMA rCAR-T cells BCMA (B-cell maturation antigen RNA Car T-Cells directed against BCMA leading to elimination of plasma cells expressing BCMA Phase 1b/2a study published [ 135 ]; phase 2b ongoing; NCT04146051 AChR, MuSK, seronegative Anti-CD19 CAR T cells Fully human autologous anti-CD19 CAR T cells CD19 DNA CAR-T cells directed against CD19 leading to depletion of CD19 positive B cells Case reports in MG [ 136 ] Phase 2, open-label study starting in 2024; (KYV-101; NCT06193889 ) Phase 1/2 open-label study starting in 2024; (CABA-201; NCT06359041 ) AChR and 2 cases co-diagnosis AChR-ab+ gMG & VGCC-ab+ LEMS ab antibody, AChR acetylcholine receptor, APRIL a proliferating-inducing ligand, BAFF B-cell activating factor, BCMA B-cell maturation antigen, BlyS B-lymphocyte stimulator, BTK Bruton’s tyrosine kinase, CAR chimeric antigen receptor, gMG generalised myasthenia gravis, IgG immunoglobulin G, IgG4P IgG4 with a proline substitution, IL-6R interleukin 6 receptor, LEMS Lambert–Eaton myasthenic syndrome, LRP4 low-density lipoprotein receptor-related protein 4, MG myasthenia gravis, MuSK muscle-specific tyrosine kinase, TNF tumour necrosis factor, VGCC voltage-gated calcium channel, VHH heavy-chain variable region antigen-binding fragment

Complement Inhibition

Approximately 80% of patients with MG have detectable AChR-ab, which belong to the IgG1 (–3) subtype. Their pathophysiological role is mediated through several different processes: blockade, accelerated endocytosis and degradation of acetylcholine receptors, but also complement-mediated membrane damage and inflammation. By targeting the central complement component C5, the terminal part of the complement cascade is inhibited, leading to reduced formation of the membrane attack complex (MAC or sC5b-9) [ 49 ]. Alternate strategies being investigated for treatment of MG are the inhibition of complement factor D [ 50 ] and complement factor B. The main risk factor for complement-inhibitor-therapy is the elevated risk of meningococcal infection, which must be mitigated by vaccination.

Complement Inhibitors in Clinical Use

Eculizumab (Anti-C5)

In 2017, the monoclonal antibody eculizumab became the first C5 inhibitor to gain regulatory approval for the therapy of treatment-refractory gMG on the basis of the REGAIN trial results. Although eculizumab did not achieve the primary endpoint compared with placebo (26 weeks of follow-up, 63 eculizumab and 62 placebo patients; change from baseline to week 26 in MG-ADL, measured by worst-rank analysis of covariance [ANCOVA]), relevant secondary endpoints and responder analyses (including MG-ADL, QMG and MG-QoL15) were positive [ 12 ]. In subsequent phase 3 gMG trials, the critical worst-rank ANCOVA approach of REGAIN was no longer used as the primary endpoint, but the secondary endpoints including the statistical analyses were. Data from the open-label extension period (OLE) showed a significant reduction in rate of exacerbations, rescue therapies and hospitalisation [ 51 ]. Further analysis of the REGAIN and REGAIN OLE also showed a greater reduction of fatigue for the eculizumab group that correlated with clinical improvement of MG and was sustained through the 52 weeks OLE period [ 52 ]. Additionally, case reports have shown efficacy of eculizumab in patients with ventilator-dependent MG [ 53 – 55 ]. Recently, data from a phase 3, open-label study on eculizumab in jMG showed efficacy in both primary endpoints (QMG and MG-ADL) [ 56 ]. This led to regulatory approval of eculizumab for jMG in Europe in 2023. Eculizumab has shown a good safety profile (most frequent AEs: infections, headache, diarrhoea and nausea) and is administered intravenously every 2 weeks (after an induction period of four weekly doses).

Ravulizumab (Anti-C5)

Ravulizumab is a monoclonal antibody that has been developed by introducing changes to the structure of eculizumab with the goal of a prolonged half-life. The prolonged half-life is achieved through enhanced FcRn binding and recycling of drug but makes the binding of C5 slightly weaker and pH dependent [ 57 ]. Ravulizumab showed efficacy versus placebo in the primary endpoints (MG-ADL and QMG) of the CHAMPION MG trial (26 weeks, 86 ravulizumab, 89 placebo) and subsequently gained regulatory approval in 2022 [ 58 ]. A post hoc sub-group analysis found no difference in clinical response to ravulizumab comparing disease duration of ≤ 2 years versus > 2 years before start of treatment [ 59 ]. A further post hoc analysis examined the time from starting treatment to a relevant clinical response. According to this analysis, the median time to minimal clinically important differences, as measured by MG-ADL (≥ 3 points), was approximately 2 weeks, and as measured by the QMG (≥ 5 points), was approximately 4 weeks [ 60 ]. Ravulizumab has shown a good safety profile (most frequent AEs: headache, diarrhoea and nausea) and is administered intravenously every 8 weeks (after induction doses at week 0 and 2).

Zilucoplan (Anti-C5/C5b)

Zilucoplan is a short macrocyclic peptide that targets C5 and additionally C5b and sterically hinders binding of C5b to C6, therefore preventing formation of the membrane attack complex in two ways [ 61 ]. Zilucoplan showed efficacy versus placebo in the primary endpoint (MG-ADL) and secondary endpoints (QMG) of the RAISE trial (12 weeks, 86 zilucoplan, 88 placebo) [ 62 ]. Zilucopan has shown a good safety profile (most frequent AEs: injection-site reactions, headache and diarrhoea) and is self-administered as a once-daily subcutaneous injection. Data from an interim-analysis of the OLE of the RAISE trial ( NCT04225871 ) after a median of 1.2 years of zilucoplan treatment continue to show a similar safety profile and overall good efficacy with rapid improvement for the group switching from placebo to zilucoplan [ 63 ]. Additionally, data from a post hoc analysis of the RAISE trial and the RAISE OLE data showed that zilucoplan improved the fatigue score over 12 weeks compared with placebo and these improvements continued over the 60 week OLE period, with 65% of patients achieving only mild or no fatigue [ 64 ].

Complement Inhibitors with Emerging Evidence

Gefurulimab (Anti-C5)

Gefurulimab (ALXN1720) is a bispecific anti-C5 and anti-human serum albumin heavy-chain variable region antigen-binding fragment (VHH) antibody fragment. Its main advantage over existing C5-inhibitors could be the subcutaneous injection paired with a longer half-life (injections once weekly) [ 65 ]. A randomised controlled phase 3 trial is currently ongoing ( NCT05556096 ).

Pozelimab with Cemdisiran (Anti-C5/C5-RNA)

The combination of pozelimab with cemdisiran explores a different concept by co-administering a C5-inhibitor (pozelimab) with a small synthetic interfering ribonucleic acid (siRNA) (cemdisiran). Cemdisiran suppresses hepatic production of C5. Both drugs are administered as subcutaneous injections. Pozelimab has gained regulatory approval for treatment of CD55-deficient protein-losing enteropathy (CHAPLE disease) and the combination of pozelimab with cemdisiran is being investigated for PNH and MG [ 66 , 67 ]. A randomised controlled phase 3 trial in MG is currently ongoing ( NCT05070858 ).

Iptacopan (Anti-Factor B)

Iptacopan (LNP023) is a complement factor-B inhibitor and targets the alternative pathway. More specifically, the inhibition of factor B blocks the activity of the alternative pathway-related C3 convertase [ 68 , 69 ]. Iptacopan is a small molecule that is administered orally. It has received regulatory approval for IgA-Nepropathy. A randomised controlled phase 3 trial in MG is currently ongoing ( NCT06517758 ).

Vemircopan (Anti-Factor D)

Vemircopan (ALXN2050) is a complement factor-D inhibitor and thus targets the alternative pathway and specifically the amplification loop of the alternative pathway [ 70 ]. It is a small molecule that is administered orally. The phase 2 trial for MG ( NCT05218096 ) was stopped at the sponsor’s decision after an interim analysis and no results are available at the time of writing.

FcRn Inhibition

FcRn is an MHC class I ­like molecule expressed in many cell types. Its importance as a target for immunomodulating therapies is derived from the role it plays in IgG recycling. FcRn transports IgG (and albumin) across endothelial cells and thus prolongs their half-life substantially. The drawback of this important mechanism is the increase in the half-life of pathogenic autoantibodies in IgG-mediated diseases. Drugs targeting FcRn lead to increased degradation of endogenous IgG, including pathogenic autoantibodies [ 71 ].

FcRn Inhibitors in Clinical Use

Efgartigimod (Anti-FcRn)

Efgartigimod is a Fc-antibody fragment that targets FcRn and reduces IgG levels by about 60–70%. Unlike full monoclonal antibodies targeting FcRn, efgartigimod retains the pH-dependent binding that allows recycling of efgartigimod and prolongs its half-life [ 72 ]. Efgartigimod showed efficacy versus placebo in the primary endpoint (≥ 2-point MG-ADL improvement sustained for ≥ 4 weeks in the first treatment cycle) of the ADAPT MG trial (26 weeks, 84 efgartigimod, 83 placebo) [ 73 ]. A total of 77% of patients were AChR-ab+, 4% were MuSK-ab+ and 19% were seronegative. In Europe and the USA, efgartigimod was approved only for AChR-ab+ MG, whereas in Japan, the approval includes MuSK-ab+ and seronegative MG. The subcutaneous formulation showed similar efficacy to the intravenous formulation in a non-inferiority trial (ADAPT-SC) [ 74 ]. Efgartigimod has shown a good safety profile (most frequent AEs: infections, headache and nausea; subcutaneous administration: additionally, injection-site reactions). It can be administered intravenously or subcutaneously in a cyclic manner (4 weekly administration followed by a drug-free interval of at least 4 weeks) [ 73 – 75 ]. Further trials to investigate other administration schemes (such as continuous administration every 2 weeks without an interval) are underway ( NCT04980495 ; ADAPT-NXT).

Rozanolixizumab (Anti-FcRn)

Rozanolixizumab is a humanised monoclonal antibody that targets the IgG binding region of FcRn and reduces IgG by about 60–70%. Rozanolixizumab showed efficacy in both treatment arms versus placebo in the primary endpoint (change in MG-ADL from baseline to day 43) of the MycarinG trial (14 weeks consisting of 6 treatment weeks and 8 observation weeks, 66 rozanolixizumab 7 mg/kg, 67 rozanolixizumab 10 mg/kg, 67 placebo) [ 76 ]. In total, 90% of patients were AChR-ab positive and 11% were MuSK-ab positive. Rozanolixizumab has gained regulatory approval for both AChR- and MuSK-ab+ gMG in Europe and the USA, and is therefore the first monoclonal antibody with regulatory approval for MuSK-ab+ gMG. Rozanolixizumab has shown an acceptable safety profile (most frequent AEs: headache, diarrhoea, pyrexia and nausea) [ 76 , 77 ]. A recent meta-analysis comparing trial data of 4 FcRn-inhibitors, however, reported a signal that rozanolixizumab showed a higher risk of mild and moderate AEs than placebo [ 78 ]. It is administered subcutaneously by pump infusion in a cyclic manner (six weekly administration followed by a variable drug-free interval). Due to the short duration of the phase 3 trial and the reported signal of higher risk of mild-to-moderate AEs in the meta-analysis, more data on the safety of rozanolixizumab is needed and could be provided by the OLE trials currently underway ( NCT04124965 completed, and most participants rolled over to NCT04650854 ).

FcRn Inhibitors with Emerging Evidence

Batoclimab (Anti-FcRn)

Batoclimab is a fully human monoclonal antibody that targets FcRn and is being developed as a low-volume subcutaneous (SC) injection. It has been shown to reduce IgG levels by about 70% [ 79 , 80 ]. Results from a phase 3 trial conducted at 27 centres only in China ( NCT05039190 ) are already available (67 batoclimab and 65 placebo). Batoclimab showed efficacy versus placebo in the primary outcome (sustained MG-ADL improvement, defined as ≥ 3-point reduction in MG-ADL score from baseline for at least 4 consecutive weeks, in the first cycle). The trial consisted of a 6-week treatment period with weekly dosing followed by a 4-week observation period and an optional second treatment cycle (which was required by 88% of patients). Most frequently reported AEs were infections, peripheral oedema, diarrhoea, MG worsening and hypercholesterolemia [ 79 ]. The currently ongoing randomised controlled phase 3 FLEX trial in the USA, Europe and Japan has a duration of 24 weeks (12-week placebo- controlled induction period and 12-week maintenance period) and is assigning patients to three groups: batoclimab 680 mg once weekly, batoclimab 340 mg once weekly or placebo once weekly ( NCT05403541 ). It is planned that two long-term extension periods over 52 weeks are to follow [ 81 ].

Nipocalimab (Anti-FcRn)

Nipocalimab is an aglycosylated monoclonal antibody that targets the IgG binding site of the FcRn and is being developed as an intravenous infusion every 2 weeks. A phase 2 trial ( NCT03772587 ; Vivacity-MG) with 68 patients who were treated over 8 weeks used a five-arm dose and administration scheme finding design (placebo, nipocalimab 5 mg/kg every 4 weeks, nipocalimab 30 mg/kg every 4 weeks, nipocalimab 60 mg/kg once, nipocalimab 60 mg/kg every 2 weeks). No new safety concerns were identified; the most common adverse events were diarrhoea, headache and nasopharyngitis. Nipocalimab did not significantly improve MG-ADL at any individual dose when comparing each dosing arm with placebo. However, if all the dosing arms were combined and compared with placebo, there was a statistically significant improvement in MG-ADL versus the placebo group. The authors concluded that this warranted further evaluation of nipocalimab for gMG [ 82 ]. A meta-analysis comparing four FcRn-inhibitors has reviewed the available data and concluded that Nipocalimab failed to show efficacy over placebo [ 78 ]. A randomised controlled phase 3 trial (placebo versus nipocalimab 60 mg/kg every 2 weeks) has been completed ( NCT04951622 ). Preliminary results have been presented at the Congress of the European Academy of Neurology in July 2024 showing that nipocalimab has reached its primary endpoint of significant MG-ADL improvement and significant improvement in QMG (secondary endpoint) compared with placebo. Peer-reviewed published results are expected soon.

B-Cell and Plasma-Cell Targeting

B cells and plasma cells play an important role in the pathogenesis of MG. They are involved in antigen presentation, autoantibody production and cytokine production. Therefore, therapeutic approaches targeting surface structures (CD 19/20 for B cells and CD 38 for plasma cells) and subsequently depleting B or plasma cells, as well as cytokine-mediated (BAFF/BlyS) approaches, are expected to be effective in MG.

B-Cell and Plasma-Cell Inhibitor in Clinical Use

Rituximab (Anti-CD20)

Rituximab is a chimeric mouse/human monoclonal antibody that targets the B cell surface antigen CD20, which is expressed on most B cells except early development pre-B cells and long-lived plasma cells. The latter is especially important, because long-lived plasma cells produce antibodies. Rituximab depletes CD20 positive B cells primarily by complement-mediated cytotoxicity. The effect lasts approximately 6–12 months. It was first used in treatment of non-Hodgkin’s lymphoma and has since been used successfully (but off label) for many autoimmune diseases [ 8 ]. Due to its chimeric nature, it carries an increased risk of allergic reactions and is therefore administered with an anti-allergic premedication. Further, the risk of reactivation of hepatitis-B-virus infection and rare reports of progressive multifocal leukoencephalopathy (PML), especially when combined with other immunosuppressants, have to be taken into account [ 83 , 84 ].

Rituximab has been administered to patients with AChR-ab+ and MuSK-ab+ MG who did not reach substantial disease stability under standard treatment, including juvenile MG [ 8 , 85 , 86 ]. Especially in MuSK-ab+ MG, rituximab is an important treatment option as reported in a systematic review [ 8 ]. Additionally, a multicentre, blinded prospective review evaluating the treatment of 119 MuSK-ab+ patients provided class IV evidence that rituximab increased the probability of a favourable outcome [ 9 ]. A further meta-analysis reviewing 24 studies involving 417 patients found that overall, 64% of patients achieved minimal manifestation state or better with a higher proportion of MuSK-ab positive than AChR-positive patients [ 87 ]. However, data from a randomised controlled phase 2 trial (BeatMG) in AChR-ab+ MG over a period of 52 weeks (27 placebo, 24 rituximab) failed to show efficacy for rituximab in the primary endpoint (combined outcome of ≥ 75% reduction of daily prednisone dose with clinical improvement or stability defined as ≤ 2-point increase in MGC score) [ 10 ]. In a more pragmatic trial, the randomised, placebo-controlled RINOMAX trial, which compared rituximab with placebo in newly diagnosed AChR-ab+ gMG over 16 weeks (rituximab 25, placebo 22), a greater proportion in the rituximab group reached minimal disease manifestation (defined as QMG ≤ 4 and daily prednisolone ≤ 10 mg and no rescue treatment) [ 11 ]. The RINOMAX trial was based on retrospective data that showed that rituximab might be more efficient in early onset MG [ 88 ]. In summary, the evidence on rituximab therapy in MG remains heterogenous and large randomised controlled trials are lacking.

B-Cell and Plasma-Cell Inhibitors in Single Cases

Obinutuzumab and Ofatumumab (Anti-CD 20)

There are single case reports on the successful use of the more modern anti-CD 20 monoclonal antibodies obinutuzumab and ofatumumab in MG [ 89 , 90 ]. Obinutuzumab has regulatory approval for chronic lymphatic leukaemia (CLL) and the reported case had concomitant MG and CLL. Ofatumumab has regulatory approval for multiple sclerosis but to date, no investigational trial has been started in MG.

Daratumumab (Anti-CD 38)

The plasma-cell-depleting anti-CD 38 antibody daratumumab has been used as off-label therapy in patients with different autoimmune diseases including MG [ 91 – 93 ]. CD 38 is expressed on plasma cells and plasmablasts, but also on natural killer (NK) cells and subpopulations of regulatory T cells [ 94 ], making it a promising target for treating autoimmune diseases. Daratumumab has regulatory approval for treatment of multiple myeloma. Its use in autoimmune diseases has only been considered in cases that were unresponsive to first- and second-line as well as escalation immunotherapies. The main reasoning behind its use is the fact that it targets plasma cells responsible for production of autoantibodies, including pathogenic antibodies. Supportive of this hypothesis are the findings of a retrospective case series in different autoimmune diseases which found that daratumumab therapy led to a marked reduction in pathogenic antibody titres [ 93 ]. No randomised controlled trials in MG have been registered.

Bortezomib (Proteasome Inhibitor)

Bortezomib is a proteasome inhibitor that leads to apoptosis in cells that have a high protein turnover. This mechanism of action means that not only tumour cells, but also plasma cells, that have a high protein turnover due to constant secretion of antibodies are sensitive to bortezomib. Bortezomib is approved as first-line therapy in multiple myeloma [ 95 , 96 ]. After experimental evidence in MG models [ 97 ], single case reports in MG exist [ 98 , 99 ]. Of note, both reported cases were MuSK-ab positive. However, this might be due to the limited on-label escalation treatment options for this MG sub-group. The unicentric, non-randomised, non-placebo controlled phase 2a (TAVAB) trial that planned to investigate the use of Bortezomib in antibody-mediated autoimmune diseases (SLE, RA and MG) was terminated due to recruitment difficulties ( NCT02102594 ) [ 100 ]. No further investigational trials in MG have been registered.

B-Cell and Plasma-Cell Inhibitors with Emerging Evidence

Inebilizumab (Anti-CD19)

Inebilizumab is a humanised anti-CD19 monoclonal antibody that depletes CD19-expressing B cells. This includes a broad spectrum of B cells including CD19-positive subpopulations of (auto)antibody-producing plasma cells [ 101 ]. On the basis of the results of a randomised controlled phase 2/3 trial (N-MOmentum; NCT02200770 ) in neuromyelitis optica spectrum disorder (NMOSD), it has received regulatory approval for NMOSD in the USA and Japan in 2020 [ 102 , 103 ]. Inebilizumab is contraindicated in patients with active hepatitis B virus (HBV) infection and active or untreated latent tuberculosis. A randomised controlled phase 3 trial in AChR-ab+ and MuSK-ab+ MG (MINT trial) has been completed (NCT0452427). In October 2024, at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, first positive results from the MINT trial were presented, demonstrating that, compared with placebo, inebilizumab significantly improved MG-ADL (primary endpoint) and QMG (secondary endpoint) over the 26-week study period in patients with gMG, including the AChR-ab+ and MuSK-ab+ sub-groups. No new safety concerns were identified. The study also included a protocol-driven steroid tapering to 5 mg prednisone per day by week 24. Published, peer-reviewed results are expected soon.

Targeting BAFF/BLyS and APRIL

The tumour necrosis factor (TNF) family ligands B-cell activating factor (BAFF) (also called B-lymphocyte stimulator [BLyS]) and a proliferating-inducing ligand (APRIL) play an important role in B-cell survival and regulation [ 104 ]. BAFF/BLyS and APRIL interact with three receptors: transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA) and the BAFF-Receptor. The BAFF–APRIL subfamily of ligands is a promising target for the treatment of autoimmune diseases, since there is evidence in mice that certain (but not all) autoreactive B cells have a greater dependency on BAFF/BLyS for their survival than non-autoreactive B cells [ 105 ].

Belimumab (Anti-BAFF/BlyS)

Belimumab (formerly LymphoStat B) is a monoclonal antibody directed against soluble BAFF/BLyS and thus inhibits B-cell proliferation and maturation [ 106 ]. Belimumab is approved for SLE since 2011 on the basis of the results of two phase 3 trials (BLISS-52 with 865 participants and BLISS-76 with 819 participants) [ 105 , 107 , 108 ]. However, a randomised controlled phase 2 trial in MG with 40 participants (placebo 22, belimumab 18) failed to show efficacy of belimumab in the primary endpoint defined by improvement of QMG score [ 109 ].

Telitacicept/RC18 (Anti-BAFF/BlyS and APRIL)

Telitacicept (also known as RC18) is a fully human TACI-Fc fusion protein that targets BAFF/BLyS and APRIL, thereby inhibiting B-cell proliferation and maturation. Telitacicept has been approved for the treatment of SLE in China in 2021 [ 110 ]. Telitacicept was safe and well tolerated in a phase II study of 29 patients and reduced clinical severity (QMG) up to week 24 [ 111 ] ( NCT04302103 ). No results were available at the time of writing. A randomised controlled phase 3 trial including AChR-ab+ and MuSK-ab+ patients is starting in 2024 ( NCT06456580 ).

Tolebrutinib (Anti-BTK)

Bruton’s tyrosine kinase (BTK) inhibitors are being investigated for use in several autoimmune and mast cell driven diseases. BTK is an important link between cell-surface receptors and downstream signalling pathways and plays an important role in B‐cell development, migration and activation [ 112 , 113 ]. Tolebrutinib is a small molecule that is being administered orally and was being investigated for use in MG. However, the phase 3 trial ( NCT05132569 ) was placed on partial clinical hold in 2022 by the US Food and Drug Administration (FDA) on the basis of a limited number of cases of drug-induced liver injury in other tolebrutinib-trials. The study was then terminated by the sponsor for strategic reasons after enrolling only six patients, while other tolebrutinib-trials resumed activity after protocol amendments.

Mezagitamab/TAK-079 (Anti-CD 38)

Mezagitamab (also known as TAK-079) is human monoclonal antibody (mAb) that targets CD38, which is expressed on antibody-producing plasmablasts and plasma cells [ 94 ]. A phase 2 trial over 16 weeks (12 placebo, 12 mezagitamab 300 mg, 12 mezagitamab 600 mg) has been completed and negative results for MG-ADL and QMG have been posted on clinicaltrials.gov but not yet published ( NCT04159805 ). The results have, however, been analysed within a Bayesian network analysis comparing 11 antibody-treatments for MG with data from randomised controlled trials. In this comparative analysis, mezagitamab ranked on the lower end for both efficacy outcomes and safety [ 114 ].

B- and T-Cell Targeting Drug with Emerging Evidence

Cladribine

Cladribine is a purine analogue that selectively depletes B and T cells. Cladribine has successfully been used in relapsing-remitting multiple sclerosis (RRMS) [ 115 ] and long-term observation studies have shown an acceptable efficacy/safety profile [ 116 ]. Results of a prospective open-label study in 13 difficult-to-treat cases of MG provided evidence of efficacy of subcutaneous cladribine: after 6 months of treatment 11 participants demonstrated significant clinical improvement, defined as a reduction of ≥ 3 points on the Myasthenia Gravis Composite scale [ 117 ]. A case report of a patient with RRMS treated with cladribine who subsequently developed concomitant AChR-ab+ MG with severe myasthenic crisis despite low B and T cell counts [ 118 ] should caution the use of cladribine in MG until further evidence can be provided. A phase 3 trial investigating the efficacy and safety of a new oral cladribine formulation in gMG in comparison with placebo has been launched in 2024 ( NCT06463587 ).

T-Cell Targeting Drug with Emerging Evidence

To date, no T-cell targeting therapy has been approved in MG. One possible target structure is CD 40, a surface molecule expressed on T cells. The CD40 dependent pathway plays an important role in T-cell-dependent immune responses, antigen presenting cell function and development of humoral memory [ 119 ].

Iscalimab/CFZ533 (Anti-CD 40)

Iscalimab (formerly known as CFZ533) is a human monoclonal antibody that targets CD 40. It leads to a blocking of the CD 40 dependent pathway while it does not deplete CD40-positive cells. Iscalimab has been investigated in a randomised controlled phase 2 trial (22 placebo, 22 iscalimab) over 52 weeks, where it failed to show efficacy over placebo in the primary endpoint (improvement in QMG score at week 25). There was, however, a signal that it improved secondary outcomes (MG-ADL and MGC) in the sub-group of non-thymectomised patients ( NCT02565576 ) [ 120 ]. Therefore, further randomised controlled trials are needed to evaluate this therapeutic strategy in MG.

Cytokine-Targeting Drugs with Emerging Evidence

Another strategy under investigation is targeting the interleukin-6 receptor (IL-6R). IL-6 is a pro-inflammatory cytokine produced by different cells including B and T cells and binds to membrane-bound IL-6R and soluble IL-6R. The IL-6 pathway is involved in several processes involved in disease pathogenesis in autoimmune diseases, such as activation and differentiation of naive T cells into pro-inflammatory helper T cells and differentiation of B cells into antibody-producing plasmablasts [ 121 , 122 ]. In MG, treatment-naïve patients displayed elevated levels of IL-6, which decreased with immunosuppressive treatment and corresponded to disease activity [ 123 ].

Satralizumab (IL6-Receptor)

Satralizumab is a humanised monoclonal antibody that targets the interleukin 6 receptor (IL6-R) and inhibits T-cell activation and differentiation as well as differentiation of B cells into plasmablasts. It has been approved for the treatment of seropositive NMOSD [ 121 ]. In MG, a randomised controlled phase 3 trial (LUMINESCENCE) has been completed and baseline characteristics of the study are available as abstract ( NCT04963270 ). The study has enrolled 186 participants and included patients with AChR-ab, MuSK-ab and LRP4-ab. The final results are expected soon, but the authors have received the information that the sponsor is probably not going to apply for regulatory approval in MG.

Tocilizumab (IL6-Receptor)

Tocilizumab is a humanised monoclonal antibody that targets IL-6R. It is approved for treatment of rheumatoid arthritis. In MG, mainly case series and small open-label studies exist, such as a retrospective case series including five patients with AChR-ab+ MG who were all older than 65 years at disease onset and reported a favourable efficacy and safety for tocilizumab in combination with low-dose oral steroids [ 124 ]. Further, a prospective, open-label, single-arm study in 14 patients with AChR-ab+ gMG over 48 weeks reported efficacy of tocilizumab in the primary endpoint (improvement in QMG score at week 12); 12 patients achieved minimal manifestation status at the end of the study period. All reported adverse events as mild to moderate, with elevated liver enzymes and infections being the most frequent [ 125 ]. Another prospective, open-label study with a control group receiving standard treatment (20 tocilizumab, 14 control group) reported greater reduction in MG- ADL score starting week 4 and sustained through week 24 for the tocilizumab group. The most frequently reported adverse event was thrombocytopenia. All adverse events were rated mild to moderate [ 126 ].

Cell-Based Treatments in Single Cases

Autologous Haematopoietic Stem Cell Transplantation

Autologous hematopoietic stem cell transplantation (HSCT) is the only treatment option that eradicates all autoreactive T and B cells leading to a reshaping of the immune system or so-called immune resetting. HSCT is being considered in carefully selected, severe and treatment-refractory autoimmune disorders including MG. Thus far, most experience with HSCT in autoimmune disorders has been gathered for multiple sclerosis, with close to 2000 patients treated until August 2022 [ 127 ]. A major concern with HSCT is the uncertain risk–benefit ratio including the aggressive conditioning regimen resulting in systemic toxicity and elevated risk of severe infections, as well as risk of death. Potential long-term complications include secondary autoimmunity, impairment of fertility and secondary neoplasms [ 127 ].

For MG, 15 cases are reported in the literature that were AChR-ab+ (9 cases), MuSK-ab+ (4 cases) or seronegative (2 cases) [ 127 – 132 ]. Follow-up ranged from 1.5 to 10 years and most patients achieved either complete stable remission or minimal manifestation status with most being able to discontinue all MG medications. However, there is also one case of secondary autoimmune disease manifesting as new onset MG after autologous HSCT for systemic sclerosis [ 133 ].

A phase 1 trial where 9 patients were enrolled has been terminated ( NCT00424489 ) and partial results have been posted on clinicaltrials.gov but not published. According to the posted results, 3 deaths occurred (one due to high-grade lymphoma, one known diabetic on tight insulin control died of insulin overdose and one patient with prior splenectomy and thymectomy who died of sepsis bacteremia) but no further results are available at the time of writing. A phase 2 trial on autologous HSCT in 14 different autoimmune disorders, with MG being one, is currently ongoing ( NCT00716066 ).

Cell-Based Treatments with Emerging Evidence

CAR-T Cell Therapy

Similar to most treatment strategies, the concept of chimeric antigen receptor (CAR) T-cell therapy emerged from oncology and is subsequently being adapted and investigated for treatment of autoimmune diseases. CAR-T cells are genetically modified T cells that express the CAR, a synthetic receptor that enables T cells to recognise target antigens without the involvement of antigen-presenting cells. The recognition of the target antigen leads to T-cell activation and subsequently to a targeted destruction of cells expressing the antigen [ 134 ]. Different B cell targets are in therapeutic use or being investigated in trials. In MG two targets are being investigated thus far: BCMA and CD19. Safety concerns include side effects of the lymphodepleting conditioning treatment (usually fludarabine and cyclophosphamide), elevated risk of infections due to B cell depletion and associated hypogammaglobulinemia, risk of cytokine-release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS), potential malignant complications from long-term persistence of CAR-T cells and off-target toxicity. Most of these have been described in CAR-T cell therapy in autoimmune diseases but with a much lower frequency and often less severity than in cancer CAR-T cell therapy [ 134 ]. Of note, none of the reported cases in MG has reached a remission status, leaving the question open as to whether this therapy would need to be administered repeatedly.

Anti-BCMA rCAR-T Cells/Descartes-08

Descartes-08 is an approach using autologous RNA CAR-T cells (rCAR-T) that target BCMA. rCAR-T cells are engineered with RNA instead of DNA and were built upon knowledge from RNA-vaccines. By using RNA, which is temporary and non-replicable, a few issues that arise with DNA CAR-T cells are being addressed: instead of being integrated permanently into the T-cell genome and replicating with cell division, the CAR-encoding mRNA does not replicate together with the activated and proliferating rCAR T-cells. Additionally, since Descartes-08 uses an ex vivo approach, no lymphodepleting conditioning treatment is necessary prior to administration [ 135 ]. The technology was assessed in a first prospective, open-label, non-randomised phase 1b/2a study ( NCT04146051 ) that enrolled 14 patients with MG (11 AChR-ab, 2 MuSK-ab, 1 seronegative) and tested several different dosing strategies. Median follow-up was 6 months, and most participants reached an improvement in MG-ADL and QMG, however, they were not symptom free. Reported adverse effects were mostly mild (headache, nausea, fever). Two severe adverse events occurred (urticaria and myocardial infarction, the latter being deemed unrelated to Descartes-08) [ 135 ]. A phase 2b trial has been completed ( NCT04146051 ) and peer-reviewed published results are expected soon.

Anti-CD19 CAR-T Cells

Anti-CD19 CAR-T cells use the conventional DNA-based approach and are delivered following a conventional lymphodepleting regimen. Three cases with successful treatment of refractory MG have been published: the first case was a patient with severe, treatment refractory, AChR-ab+ gMG who underwent anti-CD19 CAR-T cell therapy using a second-generation anti-CD19 CAR-T construct comprising a fully human CD19 binding domain. One adverse event occurred (self-limiting and resolving grade 1 transaminitis). Reported follow-up was over 2 months, during which the patients substantially improved in arm-holding time, walking distance and QMG [ 136 ]. The two other cases had a concomitant diagnosis of AChR-ab+ gMG and VGCC-ab positive LEMS and were both regarded treatment refractory to multiple therapies. They underwent the same anti-CD19 CAR-T cell therapy regimen and achieved a substantial improvement in MG-ADL and QMG as well as walking distance over a follow-up of 2 and 6 months. Reported adverse effects were flu-like symptoms (fever, muscle and joint pain) consistent with CRS, and in addition one patient with mild arterial hypotension, graded as CRS grade 2. One patient developed minor neurological side effects (mild fatigue, dysarthria and dysgraphia) interpreted as ICANS grade 1. Side effects were successfully treated with tocilizumab, dexamethasone and additionally with anakinra in one patient. Circulating CD19+ B cells were effectively depleted in both patients, accompanied by substantial reduction in pathogenic AChR- and VGCC-ab [ 137 ].

A phase 2, open-label study (KYV-101; NCT06193889 ) as well as a phase 1/2 open-label study (CABA-201; NCT06359041 ) on autologous fully human anti-CD19 CAR-T cell therapy are about to start in 2024 ( NCT06193889 ).

Other CAR-T Cell Strategies

Other CAR-T cell strategies that are being investigated include MuSK-CAAR-T cells. These chimeric autoantibody receptor (CAAR) T cells are directed against antigen-specific B cells (in this case B cells recognising MuSK) while sparing healthy B cells. An open-label phase 1 trial is starting in 2024 ( NCT05451212 ).

Real-World Data and Meta-Analyses for New Biologicals

There is a rapidly growing body of real-world data (RWD) for the use of C5 inhibitors and FcRn inhibitors in MG; at the time of writing for eculizumab, ravulizumab and efgartigimod. RWD for rozanolixizumab and zilucoplan was not available yet and are only mentioned if they were part of a meta-analysis. Due to the high research activity in the field, this section is likely to be outdated soon.

RWD for Eculizumab

Data from the OLE period of the REGAIN trial as well as data from clinical experience with eculizumab in MG and other diseases continue to show a good safety profile with few serious adverse effects mostly related to severe infections [ 51 , 138 – 142 ]. Reported severe infections include severe pneumonia, meningococcal infections and disseminated cryptococcosis [ 139 , 140 , 143 ]. For long-term safety, there are rare reports of probable eculizumab-associated hepatotoxicity with more cases reported in children and none in MG thus far [ 144 , 145 ]. In retrospective real-world studies, eculizumab continues to show efficacy in the treatment of gMG with clinically meaningful improvement in outcome measures in 70–100% of patients, reduction of exacerbations and hospitalisations and decreased concomitant drug requirement [ 138 , 140 – 142 , 146 ]. Moreover, eculizumab has been used successfully in several cases of ventilator-dependent MG with successful weaning and significant reduction in disease burden after prolonged myasthenic crisis [ 53 – 55 , 147 – 150 ]. One retrospective cohort study comparing eculizumab with rituximab treatment in patients with treatment-refractory MG found that patients on eculizumab showed a greater reduction in clinical outcome measures, while there was no difference in the rate of myasthenic crisis [ 151 ]. Another retrospective cohort study comparing eculizumab with efgartigimod found similar efficacy for reduction in MG-ADL but a greater reduction of QMG score and a greater steroid-sparing effect in the eculizumab group [ 140 ].

RWD for Ravulizumab

Emerging RWD for ravulizumab for MG was still scarce at the time of writing. However, data from other indications (PNH and aHUS, pediatric and adult data) and first RWD from MG continues to show a good safety profile comparable to the one in the RCTs [ 152 – 156 ]. Of note, these studies include patients who switched from eculizumab to ravulizumab. Switching was performed at 2 weeks after the last eculizumab dose and was not associated with specific AEs [ 152 – 154 , 156 ]. Two small retrospective real-world studies on the use of ravulizumab in MG have been published: one included ten C5-inhibitor-naïve patients and eight patients switching from eculizumab. From the ten C5-inhibitor-naïve patients, six (60%) achieved a clinical meaningful reduction of MG-ADL (improvement of > 2 point) and eight (80%) were able to reduce their steroid dosage. One C5-inhibitor-naïve patient discontinued due to MG worsening; two of the eight patients switching from eculizumab achieved a clinical meaningful reduction of MG-ADL and three were able to reduce their steroid dosage after switching to ravulizumab. None of the switchers discontinued over an observation period of 5 months [ 156 ]. The other included 36 patients treated with eculizumab, of whom 15 switched to ravulizumab when it became available (13 discontinued eculizumab, 8 remained on eculizumab). After switching to ravulizumab, 10 remained stable, 3 improved and 2 worsened; 14 of 15 patients were asked whether they preferred ravulizumab or eculizumab overall and regarding several sub-categories including convenience, efficacy and side effects. Notably, the majority preferred ravulizumab overall and for convenience, while for efficacy preferences where evenly distributed between the two medications. For side effects, all patients rated ravulizumab and eculizumab as having the same safety profile [ 142 ]. In another prospective cohort study the short-term effects of ravulizumab (41 patients over 10 weeks) and efgartigimod (21 patients over 8 weeks) on AChR-ab effector functions, including complement activation and clinical outcome measures, were compared. Clinically meaningful improvement was observed in 44% (MG-ADL) and 29% (QMG) of patients treated with ravulizumab compared with 35% (MG-ADL) and 20% (QMG) of patients treated with efgartigimod. This was substantially less than in the corresponding RCTs. The authors attributed this partly to the short follow-up period and to the higher proportion of patients with treatment-refractory MG in the cohort. Ravulizumab reduced systemic terminal complement activation. However, in the short follow-up period, neither treatment had significant effects on complement pathways proximal to C5 or on functional capacities of AChR-ab [ 157 ].

To date, there is one reported case on the successful use of ravulizumab in crisis-like severe exacerbation (MGFA IVb) [ 158 ]. Further RWD on ravulizumab comprising larger cohorts is expected to emerge soon.

RWD for Efgartigimod

Emerging RWD for efgartigimod for MG was still scarce at the time of writing. Safety data are mainly available from the OLE periods of the ADAPT and ADAPT-SC trials (ADAPT+; NCT03770403 and ADAPT-SC+; NCT04818671 ). In ADAPT+, data from 145 patients who received at least 1 cycle of efgartigimod and up to 17 cycles corresponding to 217 participant-years of exposure continue to show the same safety profile as in the RCT [ 159 ]. In ADAPT-SC+, data from 164 patients showed similar adverse events compared with the intravenous formulation with the exception of a rate of 42% of injection-site reactions. These were however, reported to be all mild to moderate and did not lead to treatment discontinuation [ 74 ]. One small prospective study from China including 14 patients over 8 weeks (one single cycle of efgartigimod) found that 12 (86%) patients achieved MG-ADL responder status (≥ 2-point improvement) [ 160 ]. A larger prospective cohort study from China reported on 61 patients (56 AChR-ab+, 4 MuSK-ab+, 1 seronegative) who received at least one cycle of efgartigimod. A second cycle was only started in 20% of patients with a mean interval length of 6 weeks. Notably, TAMG accounted for most cases (44%, 27 out of 61), and 97% of patients achieved clinically meaningful improvement within the first cycle of efgartigimod [ 161 ]. Further, five small retrospective studies with RWD have been published, with most of them pursuing the question of finding the best individual cycle interval. In total, they report on 89 patients receiving between one and six cycles of efgartigimod. Overall, between 86% and 100% of patients achieved clinically meaningful improvements. Efgartigimod effect mostly lasted between 4 and 8 weeks, with exceptional cases of longer intervals between 12 and up to 21 weeks, and follow-up cycles were administered accordingly [ 140 , 162 – 165 ]. Reported AEs were mostly mild and similar to the RCTs, with the exception of one fatality due to respiratory insufficiency where a probable severe MG worsening combined with newly diagnosed asthma was treated too late [ 162 ].

Furthermore, one of the five retrospective studies compared eculizumab (32 patients) with efgartigimod (31 patients). The study reported similar efficacy for reduction in MG-ADL between efgartigimod and eculizumab but a lesser reduction of QMG score and a lesser steroid-sparing effect in the efgartigimod group compared with eculizumab. The study reported that patients on efgartigimod had a slightly higher probability to discontinue treatment, with the main reason being MG worsening [ 140 ]. Yet another one of the five retrospective studies reported specifically on 16 double-seronegative (AChR- and MuSK-ab negative) patients (up to six cycles of efgartigimod; median interval between cycles 6 weeks). The study found only a slight improvement in MG-ADL over the whole group and only a slight reduction in prednisolone dosage. However, mean steroid dosage was already very low at the beginning of efgartigimod treatment [ 164 ].

Moreover, 13 cases of successful use of efgartigimod after myasthenic crisis (MGFA V) and 4 cases in crisis-like severe exacerbation (MGFA IVb; including 2 cases with MuSK-ab+ MG) have been reported, with all patients weaning off artificial ventilation and achieving significant clinical improvement after the first cycle of efgartigimod [ 166 – 170 ]. Further, one retrospective study from China compared efgartigimod versus IVIG in the treatment of impending myasthenic crisis or crisis-like severe exacerbation (efgartigimod nine patients, IVIG ten patients). The study found the efgartigimod group had a greater reduction in the MG-ADL score, however, follow-up was only 4 weeks, and one upper respiratory tract infection was reported in the efgartigimod group [ 171 ].

In summary, the safety profile of efgartigimod continues to be good but identifying the best individual cycle interval continues to pose clinical challenges. The question of whether efgartigimod is a feasible treatment strategy in seronegative MG remains unanswered. Further, RWD on efgartigimod comprising larger cohorts is expected to emerge soon.

Analyses Comparing Trial Data of Different New Biologicals for MG

Several systematic reviews, meta-analyses and indirect trial data comparisons attempting to compare the available data from RCTs on new biologicals for MG have been published. In general, the evidence from these analyses should be viewed with caution as available data and definitions of endpoints in different trials show important variations which make direct comparison difficult.

An analysis comparing the RCT phase 3 data for efgartigimod (ADAPT trial) and ravulizumab (CHAMPION MG trial) concluded that efgartigimod had a significantly improved response in MG-QoL15r, MG-ADL and QMG at week 4 and at time of best response. However, if data were compared at 26 weeks, responses for MG-ADL and QMG did not differ between the two drugs [ 172 ]. A meta-analysis comparing available data on four FcRn-inhibitors (batoclimab, efgartigimod, nipocalimab, rozanolixizumab) concluded that taken together, FcRn inhibition was more efficacious than placebo. However, in the analyses for single drugs, batoclimab, efgartigimod and rozanolixizumab showed efficacy over placebo, while nipocalimab failed to show efficacy over placebo [ 78 ]. Of note, the included data on nipocalimab were from a phase 2 five-arm dose-finding trial and conclusions on efficacy of nipocalimab might not be valid. For safety, rozanolixizumab, was the only drug in the analysis that caused an increased incidence of mild and moderate adverse events [ 78 ].

A further meta-analysis comparing RCT data from six biologicals (eculizumab, ravulizumab, zilucoplan, efgartigimod, rozanolixizumab and rituximab) found no significant differences between complement inhibitors and FcRn inhibitors in their efficacy versus placebo. In this analysis, rituximab was the only drug that failed to show efficacy in MG-ADL and QMG [ 173 ].

Two Bayesian network meta-analyses attempt to compare 11 new biologicals (FcRn inhibitors batoclimab, efgartigimod, nipocalimab and rozanolixzumab; complement inhibitors eculizumab, ravulizumab and zilucoplan; B-cell targeting drugs belimumab, mezagitamab and rituximab; and T-cell targeting drug iscalimab) by using data from RCTs [ 114 , 174 ]. Both analyses included data from 13 trials, however, for eculizumab, rozanolixizumab and zilucoplan, the selected studies differed and seemingly arbitrarily included only phase 2 or phase 3 data. Moreover, the compared data includes very heterogeneous numbers of patients exposed to each drug, ranging from 18 to 96, and the trial endpoints differ substantially. This probably explains why some of the reported CIs are very broad. In our view, these analyses do not allow valid and clinically relevant conclusions on the comparison of efficacy between the different drugs.

One further network meta-analysis attempted to estimate the number needed to treat (NNT), number needed to harm (NNH) and cost per improved outcome (CPIO) for efgartigimod, rozanolixizumab, ravulizumab and zilucoplan. In this analysis, the NNT was a ≥ 3-point improvement in QMG was best for efgartigimod (2.2), followed by zilucoplan (4.0), ravulizumab (4.4) and rozanolixizumab (5.4). For different outcomes (≥ 5-point improvement in QMG, ≥ 3- or ≥ 5-point improvement in MG-ADL), NNT for efgartigimod was always lowest, but the ranking of the other agents changed. The NNH for any adverse events were similar, but here, too, efgartigimod was best. The CPIO was also lowest for efgartigimod. However, this only applies for the USA since treatment costs depend on country-specific conditions of the healthcare systems [ 175 ].

The varying outcomes when different statistical methods are employed highlight the difficulties in deriving reliable conclusions from retrospective and indirect analyses that attempt to compare different study designs and sample sizes. Therefore, it appears questionable whether meaningful conclusions should be drawn from these kind of analyses for clinical decision-making.

Clinical Decision-Making and Patient Journey with New Biologicals

In this part of the review, we propose a new treatment paradigm and a decision pathway. As evidence for these clinical considerations is mostly lacking, this should be regarded as an expert recommendation from a tertiary care centre treating a large cohort of patients with MG. However, different opinions might exist in the field, and with further evidence these might need to be refined in the near future.

The regulatory approval of several new monoclonal antibodies for MG has led to a shift from broad-spectrum immunosuppressants alone to add-on target-specific and selective immunological agents. Generally, MG treatment is becoming more personalised, considering MG subtype and personal patient preferences. Additionally, therapy should now be guided by disease activity with a shift towards a strategy similar to the ‘hit hard and early’ concept from multiple sclerosis therapy. The overarching goal is fast and effective disease control. Evidence for this strategy comes from a systematic review that associated early start of therapy after disease onset with a higher probability of remission and is corroborated for rituximab by the results of a Swedish cohort study and the RINOMAX trial and for EFT consisting of IVIG or PLEX often combined with high-dose intravenous methylprednisolone by Japanese registry data [ 11 , 43 , 88 , 176 ]. Direct evidence for a higher efficacy of C5 and FcRn inhibitors if employed early is currently lacking. However, the new agents have two main advantages: onset of action is fast and adverse effects are fewer. Importantly, these therapies are very expensive and therefore economic reasoning also plays a role in most countries.

Figure 4 gives an overview of the patient journey for gMG under the new treatment paradigm. The main novelty is that patients with high disease activity should be considered for add-on treatment with C5 inhibitors or FcRn inhibitors (if AChR-ab+) or add-on treatment with the FcRn-inhibitor rozanolixizumab (if MuSK-ab+) early in the course of their disease. Of note, the Japanese guidelines recommend to first use EFT (IVIG or PLEX in combination with high-dose steroids) before more targeted biologicals such as C5 inhibitors are employed [ 44 ]. Fig. 4 Patient journey for MG – New treatment paradigm. After diagnosis, most patients receive symptomatic treatment with acetylcholinesterase inhibitors and are started on steroids. Steroids should be tapered as fast as clinically possible (goal: ≤ 5 mg/day) and steroid-sparing immunosuppressants (or here NSIST: non-steroidal immunosuppressant therapies) should be considered early. Thymectomy is recommended in AChR-ab+ patients who fulfil criteria for prognostic importance of thymectomy and should be performed within the first 2 years after diagnosis. In LRP4-ab+ MG and seronegative MG, thymectomy might be considered in individual cases. Rescue treatment with IVIg, PLEX or IA should be initiated at any point during the disease course if it is deemed clinically necessary. In patients with high disease activity, for AChR-ab+ MG add-on C5 inhibitors or FcRn inhibitors are available. For MuSK-ab+ MG, rituximab should be considered as steroid-sparing immunosuppressant. Additionally, for MuSK-ab+ MG, the FcRn-inhibitor rozanolixizumab has regulatory approval as add-on therapy. AChE acetylcholine esterase, AChR-ab acetylcholine-receptor-antibody, IA immunoadsorption, IVIg intravenous immunoglobulins, MG myasthenia gravis, MuSK-ab muscle-specific tyrosine kinase antibody, PLEX plasmapheresis. All figures in this review have been created with biorender.com.

We would like to emphasise that biologicals should be used as therapy enhancement and not instead of standard treatment: steroids and steroid-sparing immunosuppressants should be maintained and steroids should be tapered to the lowest effective dose but not withdrawn. The main reasoning behind this recommendation is the fact that in the RCTs of eculizumab, efgartigimod, ravulizumab, rozanolixizumab and zilucoplan, up to 90% of participants continued to receive steroids and/or non-steroidal immunosuppressant therapies (NSISTs) throughout the trial period.

High disease activity has been defined in the updated German treatment guidelines for myasthenic syndromes [ 40 ], including three possible scenarios:

(a) Moderate/high MGFA status (≥ MGFA IIb) and/or at least two recurrent severe exacerbations/myasthenic crises with the need for therapeutic intervention within 1 year after diagnosis despite adequate disease-modifying and symptomatic therapy.

or

(b) Persistent symptoms relevant to daily living (≥ MGFA IIa) and severe exacerbation/myasthenic crisis within the last calendar year despite adequate disease-modifying and symptomatic therapy.

or

(c) Persistent symptoms relevant to daily living, even of the mild/moderate course type (≥ MGFA IIa), for more than 2 years despite adequate disease-modifying and symptomatic therapy.

In the absence of comparative studies and biomarkers that go beyond the autoantibody to determine the MG subtype and indicate which monoclonal antibody is most effective in which sub-group of patients, the decision as to which biological is (best) suited for which patient is left to the clinician. Additionally, patient preference regarding frequency and route of administration should be considered. In Fig. 5 we propose a decision pathway for patients with high disease activity that takes antibody type, patients’ personal preference and required vaccinations into account. This decision pathway is based on the authors’ clinical experience, the regulatory approval for the different agents in Europe and the updated German treatment guidelines for myasthenic syndromes [ 40 ]. Importantly, standard treatment with steroids (goal: < 5 mg/day) and steroid-sparing immunosuppressants should be maintained, as these biologicals are add-on options to intensify therapy. Fig. 5 Proposed clinical decision pathway for patients with high disease activity: which biological for whom? In patients with high disease activity, add-on monoclonal antibodies should be considered. Standard treatment with steroids (goal: ≤ 5 mg/day) and steroid-sparing immunosuppressants should be maintained. To decide which biological for whom, first, the antibody subtype needs to be considered. If the patient is AChR-ab positive, C5 inhibitors and FcRn inhibitors have regulatory approval. To start a C5 inhibitor, complete meningococcal vaccination is mandatory. In Germany this comprises one dose of meningococcal ACWY vaccine and two or three doses of meningococcal B vaccine. To start a FcRn inhibitor, serum IgG needs to be above 5 g/l. Patient’s preference regarding application schemes (i.v. versus s.c. and daily [zilucoplan], cyclic [efgartigimod and rozanolixizumab] or interval-based [ravulizumab and eculizumab] application schemes) should be taken into account. To attempt a prediction of the clinical response to one of the two mechanisms, for FcRn inhibitors historic response to plasmapheresis and for complement inhibitors presence of complement disposition at the neuromuscular junction in a muscle biopsy might be considered. However, we would like to emphasise, that no data exist on these clinical considerations. A switch in mode of action should be considered if one of the two mechanisms shows inefficient clinical response. The precise timing is, however, unclear. At our centre, we try to hold the patient on one biological for a minimum of 4–6 months, unless side effects or a myasthenic crisis make an earlier switch necessary. Relevant side effects should prompt an early switch to a different agent. Of note, the proposed strategy for C5 inhibitors to first use ravulizumab or zilucoplan is based on the regulatory approval in Europe: ravulizumab and zilucoplan are approved as add-on treatment in AChR-ab+ gMG, whereas in Europe, eculizumab is strictly only approved for therapy-refractory AChR-ab+ gMG. In countries where regulatory approval of eculizumab does not differ from ravulizumab, it might be reasonable to start with eculizumab first (e.g. Japan). If the patient is MuSK-ab positive, either rituximab or rozanolixizumab are valid options. In Japan, efgartigimod has also received regulatory approval for MuSK-ab+ MG. Rituximab (off-label-use in most countries including Germany) necessitates a complete vaccination status, while rozanolixizumab/efgartigimod require a serum IgG level above 5 g/l. Patient preference for a low frequency intravenous application would favour rituximab, while a preference for cyclic subcutaneous pump infusions would favour rozanolixizumab. AChR acetylcholine-receptor, MuSK-ab muscle-specific tyrosine kinase antibody, s.c. subcutaneous. *In Japan, efgartigimod has received regulatory approval for AChR-ab+, MuSK-ab+ and seronegative gMG. All figures in this review have been created with biorender.com.

Conclusions and Outlook

After decades of therapeutic stagnation, MG treatment is finally becoming more personalised, considering MG subtype and patients’ personal preferences. The regulatory approval of complement inhibitors and FcRn inhibitors as add-on treatment regimens enables a shift from broad-spectrum immunosuppressants alone to add-on targeted and selective immune modulation. Additionally, several new biologicals including B and T cell targeting and cell-based strategies such as CAR-T cell therapies are being investigated.

The availability of more targeted and fast-acting biologicals has raised the hope among patients and clinicians that a substantially larger proportion of patients will achieve satisfactory clinical improvements or even remission status. The coming years will show whether the new agents can hold that promise.

While excitement in the community about scientific advances is high, important questions remain open: when should novel agents be initiated and when discontinued (apart from lack of efficacy or side effects)? What should be the precise intervals and reasons for inter-class and intra-class switching? Are there possible synergistic or antagonistic effects between the new biologicals? Are the new agents safe over long-term periods? Are they efficient to treat seronegative MG?

Predictive biomarkers to help decide which patient might profit most from which biological are lacking, despite an intensive scientific search. As the new agents are being employed early in patients with high disease activity, more data are needed to define what ‘early’ means, for example, whether the new biologicals could and should also be employed as first-line therapies in treatment-naïve patients. Another open discussion regards the question of whether and at what dosage standard treatment should be continued together with the new biologicals.

As new evidence will hopefully shed light on some of these questions, decision pathways and treatment guidelines will need to be updated.

Declarations

Funding

Open Access funding enabled and organised by Projekt DEAL.

Authors contributions

Concept and planning of the review: L.G. and A.M.; writing of first draft: L.G.; figures: P.D.; and critical revision of the manuscript: all authors. All authors read and approved the final manuscript.

Conflict of interest

L.G. reports no conflicts of interest. P.D. received speaker´s honoraria from Alexion and UCB. S.H. received speaker´s honoraria and honoraria for attendance at advisory boards from Alexion, argenx, Roche and UCB. A. M. received speaker or consultancy honoraria or financial research support (paid to his institution) from Alexion, Argenx, Axunio, Destin, Grifols, Hormosan Pharma, Janssen, Merck, Octapharma, UCB and Xcenda. He serves as member of the medical advisory board of the German Myasthenia Gravis Society.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

No datasets were generated or analysed for this review article; data that support the findings referenced in this article can be found in their corresponding referenced original study.

Code availability

Not applicable.

References

1. Jolly F Ueber Myasthenia gravis pseudoparalytica Berliner Klinische Wochenschrift. 1895 32 1 6 Jolly F. Ueber Myasthenia gravis pseudoparalytica. Berliner Klinische Wochenschrift. 1895;32:1–6.

2. Grob D Brunner N Namba T Pagala M Lifetime course of myasthenia gravis Muscle Nerve 2008 37 2 141 149 10.1002/mus.20950 18059039 Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37(2):141–9. 18059039 10.1002/mus.20950

3. Walker MB Treatment of myasthenia gravis with physostigmine Lancet 1934 1 1200 1201 10.1016/S0140-6736(00)94294-6 Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet. 1934;1:1200–1.

4. Simpson JA Immunological disturbances in myasthenia gravis with a report of Hashimoto's disease developing after thymectomy J Neurol Neurosurg Psychiatry 1964 27 6 485 492 10.1136/jnnp.27.6.485 14249387 PMC495787 Simpson JA. Immunological disturbances in myasthenia gravis with a report of Hashimoto’s disease developing after thymectomy. J Neurol Neurosurg Psychiatry. 1964;27(6):485–92. 14249387 10.1136/jnnp.27.6.485 PMC495787

5. Palace J Newsom-Davis J Lecky B A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis Myasthenia Gravis Study Group Neurology 1998 50 6 1778 1783 10.1212/WNL.50.6.1778 9633727 Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis Myasthenia Gravis Study Group. Neurology. 1998;50(6):1778–83. 9633727 10.1212/wnl.50.6.1778

6. Tindall RS Rollins JA Phillips JT Greenlee RG Wells L Belendiuk G Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis N Engl J Med 1987 316 12 719 724 10.1056/NEJM198703193161205 3547126 Tindall RS, Rollins JA, Phillips JT, Greenlee RG, Wells L, Belendiuk G. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med. 1987;316(12):719–24. 3547126 10.1056/NEJM198703193161205

7. Meriggioli MN Sanders DB Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity Lancet Neurol 2009 8 5 475 490 10.1016/S1474-4422(09)70063-8 19375665 PMC2730933 Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475–90. 19375665 10.1016/S1474-4422(09)70063-8 PMC2730933

8. Tandan R Hehir MK 2nd Waheed W Howard DB Rituximab treatment of myasthenia gravis: a systematic review Muscle Nerve 2017 56 2 185 196 10.1002/mus.25597 28164324 Tandan R, Hehir MK 2nd, Waheed W, Howard DB. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve. 2017;56(2):185–96. 28164324 10.1002/mus.25597

9. Hehir MK Hobson-Webb LD Benatar M Barnett C Silvestri NJ Howard JF Jr Rituximab as treatment for anti-MuSK myasthenia gravis: multicenter blinded prospective review Neurology 2017 89 10 1069 1077 10.1212/WNL.0000000000004341 28801338 Hehir MK, Hobson-Webb LD, Benatar M, Barnett C, Silvestri NJ, Howard JF Jr, et al. Rituximab as treatment for anti-MuSK myasthenia gravis: multicenter blinded prospective review. Neurology. 2017;89(10):1069–77. 28801338 10.1212/WNL.0000000000004341

10. Nowak RJ Coffey CS Goldstein JM Dimachkie MM Benatar M Kissel JT Phase 2 trial of rituximab in acetylcholine receptor antibody-positive generalized myasthenia gravis: the BeatMG study Neurology 2022 98 4 e376 e389 10.1212/WNL.0000000000013121 34857535 PMC8793103 Nowak RJ, Coffey CS, Goldstein JM, Dimachkie MM, Benatar M, Kissel JT, et al. Phase 2 trial of rituximab in acetylcholine receptor antibody-positive generalized myasthenia gravis: the BeatMG study. Neurology. 2022;98(4):e376–89. 34857535 10.1212/WNL.0000000000013121 PMC8793103

11. Piehl F Eriksson-Dufva A Budzianowska A Feresiadou A Hansson W Hietala MA Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial JAMA Neurol 2022 79 11 1105 1112 10.1001/jamaneurol.2022.2887 36121672 PMC9486640 Piehl F, Eriksson-Dufva A, Budzianowska A, Feresiadou A, Hansson W, Hietala MA, et al. Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial. JAMA Neurol. 2022;79(11):1105–12. 36121672 10.1001/jamaneurol.2022.2887 PMC9486640

12. Howard JF Jr Utsugisawa K Benatar M Murai H Barohn RJ Illa I Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study Lancet Neurol 2017 16 12 976 986 10.1016/S1474-4422(17)30369-1 29066163 Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86. 29066163 10.1016/S1474-4422(17)30369-1

13. Jaretzki A 3rd Barohn RJ Ernstoff RM Kaminski HJ Keesey JC Penn AS Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America Neurology 2000 55 1 16 23 10.1212/WNL.55.1.16 10891897 Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55(1):16–23. 10891897 10.1212/wnl.55.1.16

14. Benatar M Sanders DB Burns TM Cutter GR Guptill JT Baggi F Recommendations for myasthenia gravis clinical trials Muscle Nerve 2012 45 6 909 917 10.1002/mus.23330 22581550 Benatar M, Sanders DB, Burns TM, Cutter GR, Guptill JT, Baggi F, et al. Recommendations for myasthenia gravis clinical trials. Muscle Nerve. 2012;45(6):909–17. 22581550 10.1002/mus.23330

15. Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW Reliability testing of the quantitative myasthenia gravis score Ann N Y Acad Sci 1998 841 1 769 772 10.1111/j.1749-6632.1998.tb11015.x 9668327 Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841(1):769–72. 9668327 10.1111/j.1749-6632.1998.tb11015.x

16. Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study G Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite Muscle Nerve 2008 38 6 1553 1562 10.1002/mus.21185 19016543 Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study G. Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite. Muscle Nerve. 2008;38(6):1553–62. 19016543 10.1002/mus.21185

17. Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ Myasthenia gravis activities of daily living profile Neurology 1999 52 7 1487 1489 10.1212/WNL.52.7.1487 10227640 Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999;52(7):1487–9. 10227640 10.1212/wnl.52.7.1487

18. Burns TM Sadjadi R Utsugisawa K Gwathmey KG Joshi A Jones S International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r Muscle Nerve 2016 54 6 1015 1022 10.1002/mus.25198 27220659 Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et al. International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. Muscle Nerve. 2016;54(6):1015–22. 27220659 10.1002/mus.25198

19. Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study G Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis Muscle Nerve 2008 38 2 957 963 10.1002/mus.21053 18642357 Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study G. Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve. 2008;38(2):957–63. 18642357 10.1002/mus.21053

20. Katzberg HD Barnett C Merkies IS Bril V Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial Muscle Nerve 2014 49 5 661 665 10.1002/mus.23988 24810970 Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve. 2014;49(5):661–5. 24810970 10.1002/mus.23988

21. Muppidi S Wolfe GI Conaway M Burns TM Mg C MG-ADL: still a relevant outcome measure Muscle Nerve 2011 44 5 727 731 10.1002/mus.22140 22006686 Muppidi S, Wolfe GI, Conaway M, Burns TM, Mg C. MG-ADL: still a relevant outcome measure. Muscle Nerve. 2011;44(5):727–31. 22006686 10.1002/mus.22140

22. Tubach F Ravaud P Baron G Falissard B Logeart I Bellamy N Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state Ann Rheum Dis 2005 64 1 34 37 10.1136/ard.2004.023028 15130902 PMC1755171 Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, et al. Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state. Ann Rheum Dis. 2005;64(1):34–7. 15130902 10.1136/ard.2004.023028 PMC1755171

23. Mendoza M Tran C Bril V Katzberg HD Barnett C Patient-acceptable symptom states in myasthenia gravis Neurology 2020 95 12 e1617 e1628 10.1212/WNL.0000000000010574 32759200 Mendoza M, Tran C, Bril V, Katzberg HD, Barnett C. Patient-acceptable symptom states in myasthenia gravis. Neurology. 2020;95(12):e1617–28. 32759200 10.1212/WNL.0000000000010574

24. Meisel A Sacca F Spillane J Vissing J Sub-committee MGC Expert consensus recommendations for improving and standardising the assessment of patients with generalised myasthenia gravis Eur J Neurol 2024 31 7 e16280 10.1111/ene.16280 38523419 PMC11236001 Meisel A, Sacca F, Spillane J, Vissing J, Sub-committee MGC. Expert consensus recommendations for improving and standardising the assessment of patients with generalised myasthenia gravis. Eur J Neurol. 2024;31(7): e16280. 38523419 10.1111/ene.16280 PMC11236001

25. Huijbers MG Marx A Plomp JJ Le Panse R Phillips WD Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders Lancet Neurol 2022 21 2 163 175 10.1016/S1474-4422(21)00357-4 35065039 Huijbers MG, Marx A, Plomp JJ, Le Panse R, Phillips WD. Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):163–75. 35065039 10.1016/S1474-4422(21)00357-4

26. Lehnerer S Jacobi J Schilling R Grittner U Marbin D Gerischer L Burden of disease in myasthenia gravis: taking the patient's perspective J Neurol 2022 269 6 3050 3063 10.1007/s00415-021-10891-1 34800167 PMC9120127 Lehnerer S, Jacobi J, Schilling R, Grittner U, Marbin D, Gerischer L, et al. Burden of disease in myasthenia gravis: taking the patient’s perspective. J Neurol. 2022;269(6):3050–63. 34800167 10.1007/s00415-021-10891-1 PMC9120127

27. Baggi F Andreetta F Maggi L Confalonieri P Morandi L Salerno F Complete stable remission and autoantibody specificity in myasthenia gravis Neurology 2013 80 2 188 195 10.1212/WNL.0b013e31827b907b 23255823 Baggi F, Andreetta F, Maggi L, Confalonieri P, Morandi L, Salerno F, et al. Complete stable remission and autoantibody specificity in myasthenia gravis. Neurology. 2013;80(2):188–95. 23255823 10.1212/WNL.0b013e31827b907b

28. Andersen JB Gilhus NE Sanders DB Factors affecting outcome in myasthenia gravis Muscle Nerve 2016 54 6 1041 1049 10.1002/mus.25205 27251303 Andersen JB, Gilhus NE, Sanders DB. Factors affecting outcome in myasthenia gravis. Muscle Nerve. 2016;54(6):1041–9. 27251303 10.1002/mus.25205

29. Punga AR Maddison P Heckmann JM Guptill JT Evoli A Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders Lancet Neurol 2022 21 2 176 188 10.1016/S1474-4422(21)00297-0 35065040 Punga AR, Maddison P, Heckmann JM, Guptill JT, Evoli A. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):176–88. 35065040 10.1016/S1474-4422(21)00297-0

30. Benatar M A systematic review of diagnostic studies in myasthenia gravis Neuromuscul Disord 2006 16 7 459 467 10.1016/j.nmd.2006.05.006 16793269 Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord. 2006;16(7):459–67. 16793269 10.1016/j.nmd.2006.05.006

31. Hoffmann S Harms L Schuelke M Ruckert JC Goebel HH Stenzel W Complement deposition at the neuromuscular junction in seronegative myasthenia gravis Acta Neuropathol 2020 139 6 1119 1122 10.1007/s00401-020-02147-5 32157386 PMC7244604 Hoffmann S, Harms L, Schuelke M, Ruckert JC, Goebel HH, Stenzel W, et al. Complement deposition at the neuromuscular junction in seronegative myasthenia gravis. Acta Neuropathol. 2020;139(6):1119–22. 32157386 10.1007/s00401-020-02147-5 PMC7244604

32. Finnis MF Jayawant S Juvenile myasthenia gravis: a paediatric perspective Autoimmune Dis. 2011 2011 404101 22110902 10.4061/2011/404101 PMC3206364 Finnis MF, Jayawant S. Juvenile myasthenia gravis: a paediatric perspective. Autoimmune Dis. 2011;2011: 404101. 22110902 10.4061/2011/404101 PMC3206364

33. Suzuki S Masuda M Uzawa A Nagane Y Konno S Suzuki Y Japan MG registry: chronological surveys over 10 years Clin Experiment Neuroimmunol. 2022 14 1 5 12 10.1111/cen3.12731 Suzuki S, Masuda M, Uzawa A, Nagane Y, Konno S, Suzuki Y, et al. Japan MG registry: chronological surveys over 10 years. Clin Experiment Neuroimmunol. 2022;14(1):5–12.

34. Asmail A Kesler A Kolb H Drory VE Karni A A tri-modal distribution of age-of-onset in female patients with myasthenia gravis is associated with the gender-related clinical differences Int J Neurosci 2019 129 4 313 319 10.1080/00207454.2018.1529669 30260722 Asmail A, Kesler A, Kolb H, Drory VE, Karni A. A tri-modal distribution of age-of-onset in female patients with myasthenia gravis is associated with the gender-related clinical differences. Int J Neurosci. 2019;129(4):313–9. 30260722 10.1080/00207454.2018.1529669

35. Lee I Kaminski HJ Xin H Cutter G Gender and quality of life in myasthenia gravis patients from the myasthenia gravis foundation of America registry Muscle Nerve 2018 58 1 90 98 10.1002/mus.26104 29466829 Lee I, Kaminski HJ, Xin H, Cutter G. Gender and quality of life in myasthenia gravis patients from the myasthenia gravis foundation of America registry. Muscle Nerve. 2018;58(1):90–8. 10.1002/mus.26104 29466829

36. Beland B, Perera T, Lee A, Greenfield J, Korngut L, Jewett G. No sex-based differences in odds of starting or time to treatment of generalized myasthenia gravis: a single center cohort study. Muscle Nerve. 2024;n/a(n/a). 10.1002/mus.28210 39054840

37. Funke M Eveslage M Zschuntzsch J Hagenacker T Ruck T Schubert C Fatigue and associated factors in myasthenia gravis: a nationwide registry study J Neurol 2024 271 8 5665 5670 10.1007/s00415-024-12490-2 38871821 PMC11319509 Funke M, Eveslage M, Zschuntzsch J, Hagenacker T, Ruck T, Schubert C, et al. Fatigue and associated factors in myasthenia gravis: a nationwide registry study. J Neurol. 2024;271(8):5665–70. 38871821 10.1007/s00415-024-12490-2 PMC11319509

38. Mantegazza R Antozzi C When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies Ther Adv Neurol Disord 2018 11 1756285617749134 10.1177/1756285617749134 29403543 PMC5791553 Mantegazza R, Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Ther Adv Neurol Disord. 2018;11:1756285617749134. 29403543 10.1177/1756285617749134 PMC5791553

39. Schneider-Gold C Hagenacker T Melzer N Ruck T Understanding the burden of refractory myasthenia gravis Ther Adv Neurol Disord 2019 12 1756286419832242 10.1177/1756286419832242 30854027 PMC6399761 Schneider-Gold C, Hagenacker T, Melzer N, Ruck T. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019;12:1756286419832242. 30854027 10.1177/1756286419832242 PMC6399761

40. Wiendl H Abicht A Chan A Della Marina A Hagenacker T Hekmat K Guideline for the management of myasthenic syndromes Ther Adv Neurol Disord 2023 16 17562864231213240 10.1177/17562864231213240 38152089 PMC10752078 Wiendl H, Abicht A, Chan A, Della Marina A, Hagenacker T, Hekmat K, et al. Guideline for the management of myasthenic syndromes. Ther Adv Neurol Disord. 2023;16:17562864231213240. 38152089 10.1177/17562864231213240 PMC10752078

41. Verschuuren JJ Palace J Murai H Tannemaat MR Kaminski HJ Bril V Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders Lancet Neurol 2022 21 2 189 202 10.1016/S1474-4422(21)00463-4 35065041 Verschuuren JJ, Palace J, Murai H, Tannemaat MR, Kaminski HJ, Bril V. Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):189–202. 35065041 10.1016/S1474-4422(21)00463-4

42. Menon D Bril V Pharmacotherapy of generalized myasthenia gravis with special emphasis on newer biologicals Drugs 2022 82 8 865 887 10.1007/s40265-022-01726-y 35639288 PMC9152838 Menon D, Bril V. Pharmacotherapy of generalized myasthenia gravis with special emphasis on newer biologicals. Drugs. 2022;82(8):865–87. 35639288 10.1007/s40265-022-01726-y PMC9152838

43. Uzawa A Suzuki S Kuwabara S Akamine H Onishi Y Yasuda M Effectiveness of early cycles of fast-acting treatment in generalised myasthenia gravis J Neurol Neurosurg Psychiatry 2023 94 6 467 473 10.1136/jnnp-2022-330519 36693723 Uzawa A, Suzuki S, Kuwabara S, Akamine H, Onishi Y, Yasuda M, et al. Effectiveness of early cycles of fast-acting treatment in generalised myasthenia gravis. J Neurol Neurosurg Psychiatry. 2023;94(6):467–73. 36693723 10.1136/jnnp-2022-330519

44. Murai H Utsugisawa K Motomura M Imai T Uzawa A Suzuki S The Japanese clinical guidelines 2022 for myasthenia gravis and Lambert-Eaton myasthenic syndrome Clin Exp Neuroimmunol. 2023 14 1 19 27 10.1111/cen3.12739 Murai H, Utsugisawa K, Motomura M, Imai T, Uzawa A, Suzuki S. The Japanese clinical guidelines 2022 for myasthenia gravis and Lambert-Eaton myasthenic syndrome. Clin Exp Neuroimmunol. 2023;14(1):19–27.

45. Narayanaswami P Sanders DB Thomas L Thibault D Blevins J Desai R Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study Lancet Neurol 2024 23 3 267 276 10.1016/S1474-4422(24)00028-0 38365379 Narayanaswami P, Sanders DB, Thomas L, Thibault D, Blevins J, Desai R, et al. Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study. Lancet Neurol. 2024;23(3):267–76. 38365379 10.1016/S1474-4422(24)00028-0

46. Wolfe GI Kaminski HJ Aban IB Minisman G Kuo HC Marx A Randomized trial of thymectomy in myasthenia gravis N Engl J Med 2016 375 6 511 522 10.1056/NEJMoa1602489 27509100 PMC5189669 Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511–22. 27509100 10.1056/NEJMoa1602489 PMC5189669

47. De Bleecker JL Remiche G Alonso-Jimenez A Van Parys V Bissay V Delstanche S Recommendations for the management of myasthenia gravis in Belgium Acta Neurol Belg 2024 124 4 1371 1383 10.1007/s13760-024-02552-7 38649556 PMC11266451 De Bleecker JL, Remiche G, Alonso-Jimenez A, Van Parys V, Bissay V, Delstanche S, et al. Recommendations for the management of myasthenia gravis in Belgium. Acta Neurol Belg. 2024;124(4):1371–83. 38649556 10.1007/s13760-024-02552-7 PMC11266451

48. Sanders DB Evoli A Immunosuppressive therapies in myasthenia gravis Autoimmunity 2010 43 5–6 428 435 10.3109/08916930903518107 20166870 Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010;43(5–6):428–35. 20166870 10.3109/08916930903518107

49. Kusner LL Kaminski HJ Soltys J Effect of complement and its regulation on myasthenia gravis pathogenesis Expert Rev Clin Immunol 2008 4 1 43 52 10.1586/1744666X.4.1.43 20477586 PMC4375541 Kusner LL, Kaminski HJ, Soltys J. Effect of complement and its regulation on myasthenia gravis pathogenesis. Expert Rev Clin Immunol. 2008;4(1):43–52. 20477586 10.1586/1744666X.4.1.43 PMC4375541

50. Nair SS Jacob S Novel immunotherapies for myasthenia gravis Immunotargets Ther. 2023 12 25 45 10.2147/ITT.S377056 37038596 PMC10082579 Nair SS, Jacob S. Novel immunotherapies for myasthenia gravis. Immunotargets Ther. 2023;12:25–45. 37038596 10.2147/ITT.S377056 PMC10082579

51. Muppidi S Utsugisawa K Benatar M Murai H Barohn RJ Illa I Long-term safety and efficacy of eculizumab in generalized myasthenia gravis Muscle Nerve 2019 60 1 14 24 10.1002/mus.26447 30767274 PMC6619057 Muppidi S, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Long-term safety and efficacy of eculizumab in generalized myasthenia gravis. Muscle Nerve. 2019;60(1):14–24. 30767274 10.1002/mus.26447 PMC6619057

52. Andersen H Mantegazza R Wang JJ O'Brien F Patra K Howard JF Jr Eculizumab improves fatigue in refractory generalized myasthenia gravis Qual Life Res 2019 28 8 2247 2254 10.1007/s11136-019-02148-2 30905021 PMC6620379 Andersen H, Mantegazza R, Wang JJ, O’Brien F, Patra K, Howard JF Jr, et al. Eculizumab improves fatigue in refractory generalized myasthenia gravis. Qual Life Res. 2019;28(8):2247–54. 30905021 10.1007/s11136-019-02148-2 PMC6620379

53. Usman U Chrisman C Houston D Haws CC Wang A Muley S The use of eculizumab in ventilator-dependent myasthenia gravis patients Muscle Nerve 2021 64 2 212 215 10.1002/mus.27326 34008175 Usman U, Chrisman C, Houston D, Haws CC, Wang A, Muley S. The use of eculizumab in ventilator-dependent myasthenia gravis patients. Muscle Nerve. 2021;64(2):212–5. 34008175 10.1002/mus.27326

54. Hofstadt-van Oy U Stankovic S Kelbel C Oswald D Larrosa-Lombardi S Barchfeld T Complement inhibition initiated recovery of a severe myasthenic crisis with COVID-19 J Neurol 2021 268 9 3125 3128 10.1007/s00415-021-10428-6 33537898 PMC7857861 Hofstadt-van Oy U, Stankovic S, Kelbel C, Oswald D, Larrosa-Lombardi S, Barchfeld T, et al. Complement inhibition initiated recovery of a severe myasthenic crisis with COVID-19. J Neurol. 2021;268(9):3125–8. 33537898 10.1007/s00415-021-10428-6 PMC7857861

55. Vinciguerra C Bevilacqua L Toriello A Iovino A Piscosquito G Calicchio G Starting eculizumab as rescue therapy in refractory myasthenic crisis Neurol Sci 2023 44 10 3707 3709 10.1007/s10072-023-06900-y 37306795 Vinciguerra C, Bevilacqua L, Toriello A, Iovino A, Piscosquito G, Calicchio G, et al. Starting eculizumab as rescue therapy in refractory myasthenic crisis. Neurol Sci. 2023;44(10):3707–9. 37306795 10.1007/s10072-023-06900-y

56. Brandsema JF Ginsberg M Hoshino H Mimaki M Nagata S Rao VK Eculizumab in adolescent patients with refractory generalized myasthenia gravis: a phase 3, open-label, multicenter study Pediatr Neurol 2024 156 198 207 10.1016/j.pediatrneurol.2024.04.020 38810600 Brandsema JF, Ginsberg M, Hoshino H, Mimaki M, Nagata S, Rao VK, et al. Eculizumab in adolescent patients with refractory generalized myasthenia gravis: a phase 3, open-label, multicenter study. Pediatr Neurol. 2024;156:198–207. 38810600 10.1016/j.pediatrneurol.2024.04.020

57. Sheridan D Yu ZX Zhang Y Patel R Sun F Lasaro MA Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action PLoS ONE 2018 13 4 e0195909 10.1371/journal.pone.0195909 29649283 PMC5897016 Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, et al. Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action. PLoS ONE. 2018;13(4): e0195909. 29649283 10.1371/journal.pone.0195909 PMC5897016

58. Vu T Meisel A Mantegazza R Annane D Katsuno M Aguzzi R Terminal complement inhibitor ravulizumab in generalized myasthenia gravis NEJM Evid. 2022 1 5 66 10.1056/EVIDoa2100066 38319212 Vu T, Meisel A, Mantegazza R, Annane D, Katsuno M, Aguzzi R, et al. Terminal complement inhibitor ravulizumab in generalized myasthenia gravis. NEJM Evid. 2022;1(5):66. 10.1056/EVIDoa2100066 38319212

59. Howard JF Jr Vu T Mantegazza R Kushlaf H Suzuki S Wiendl H Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: a post hoc subgroup analysis of the CHAMPION MG study Muscle Nerve 2024 69 5 556 565 10.1002/mus.28044 38380691 Howard JF Jr, Vu T, Mantegazza R, Kushlaf H, Suzuki S, Wiendl H, et al. Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: a post hoc subgroup analysis of the CHAMPION MG study. Muscle Nerve. 2024;69(5):556–65. 38380691 10.1002/mus.28044

60. Habib AA Benatar M Vu T Meisel A Attarian S Katsuno M Time to response with ravulizumab, a long-acting terminal complement inhibitor, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis Eur J Neurol 2024 31 12 e16490 10.1111/ene.16490 39373062 PMC11555155 Habib AA, Benatar M, Vu T, Meisel A, Attarian S, Katsuno M, et al. Time to response with ravulizumab, a long-acting terminal complement inhibitor, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. Eur J Neurol. 2024;31(12): e16490. 39373062 10.1111/ene.16490 PMC11555155

61. Shirley M Zilucoplan: first approval Drugs 2024 84 1 99 104 10.1007/s40265-023-01977-3 38093160 PMC10925559 Shirley M. Zilucoplan: first approval. Drugs. 2024;84(1):99–104. 38093160 10.1007/s40265-023-01977-3 PMC10925559

62. Howard JF Jr Bresch S Genge A Hewamadduma C Hinton J Hussain Y Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study Lancet Neurol 2023 22 5 395 406 10.1016/S1474-4422(23)00080-7 37059508 Howard JF Jr, Bresch S, Genge A, Hewamadduma C, Hinton J, Hussain Y, et al. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023;22(5):395–406. 37059508 10.1016/S1474-4422(23)00080-7

63. Howard JF Jr Bresch S Farmakidis C Freimer M Genge A Hewamadduma C Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study Ther Adv Neurol Disord 2024 17 17562864241243186 10.1177/17562864241243186 38638673 PMC11025429 Howard JF Jr, Bresch S, Farmakidis C, Freimer M, Genge A, Hewamadduma C, et al. Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study. Ther Adv Neurol Disord. 2024;17:17562864241243186. 38638673 10.1177/17562864241243186 PMC11025429

64. Weiss MD Freimer M Leite MI Maniaol A Utsugisawa K Bloemers J Improvement of fatigue in generalised myasthenia gravis with zilucoplan J Neurol 2024 271 5 2758 2767 10.1007/s00415-024-12209-3 38400914 PMC11055786 Weiss MD, Freimer M, Leite MI, Maniaol A, Utsugisawa K, Bloemers J, et al. Improvement of fatigue in generalised myasthenia gravis with zilucoplan. J Neurol. 2024;271(5):2758–67. 38400914 10.1007/s00415-024-12209-3 PMC11055786

65. Jindal S Pedersen DV Gera N Chandler J Patel R Neill A Characterization of the bispecific VHH antibody gefurulimab (ALXN1720) targeting complement component 5, and designed for low volume subcutaneous administration Mol Immunol 2024 165 29 41 10.1016/j.molimm.2023.12.004 38142486 Jindal S, Pedersen DV, Gera N, Chandler J, Patel R, Neill A, et al. Characterization of the bispecific VHH antibody gefurulimab (ALXN1720) targeting complement component 5, and designed for low volume subcutaneous administration. Mol Immunol. 2024;165:29–41. 38142486 10.1016/j.molimm.2023.12.004

66. Devalaraja-Narashimha K Huang C Cao M Chen YP Borodovsky A Olson WC Pharmacokinetics and pharmacodynamics of pozelimab alone or in combination with cemdisiran in non-human primates PLoS ONE 2022 17 6 e0269749 10.1371/journal.pone.0269749 35709087 PMC9202903 Devalaraja-Narashimha K, Huang C, Cao M, Chen YP, Borodovsky A, Olson WC, et al. Pharmacokinetics and pharmacodynamics of pozelimab alone or in combination with cemdisiran in non-human primates. PLoS ONE. 2022;17(6): e0269749. 35709087 10.1371/journal.pone.0269749 PMC9202903

67. Hoy SM Pozelimab: first approval Drugs 2023 83 16 1551 1557 10.1007/s40265-023-01955-9 37856038 Hoy SM. Pozelimab: first approval. Drugs. 2023;83(16):1551–7. 37856038 10.1007/s40265-023-01955-9

68. Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, et al. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N Engl J Med. 2024. 10.1056/NEJMoa2410316 39453772

69. Schubart A Anderson K Mainolfi N Sellner H Ehara T Adams CM Small-molecule factor B inhibitor for the treatment of complement-mediated diseases Proc Natl Acad Sci U S A 2019 116 16 7926 7931 10.1073/pnas.1820892116 30926668 PMC6475383 Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A. 2019;116(16):7926–31. 30926668 10.1073/pnas.1820892116 PMC6475383

70. Harboe M Ulvund G Vien L Fung M Mollnes TE The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation Clin Exp Immunol 2004 138 3 439 446 10.1111/j.1365-2249.2004.02627.x 15544620 PMC1809239 Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin Exp Immunol. 2004;138(3):439–46. 15544620 10.1111/j.1365-2249.2004.02627.x PMC1809239

71. Kuo TT Baker K Yoshida M Qiao SW Aveson VG Lencer WI Neonatal Fc receptor: from immunity to therapeutics J Clin Immunol 2010 30 6 777 789 10.1007/s10875-010-9468-4 20886282 PMC2970823 Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, et al. Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol. 2010;30(6):777–89. 20886282 10.1007/s10875-010-9468-4 PMC2970823

72. Wolfe GI Ward ES de Haard H Ulrichts P Mozaffar T Pasnoor M IgG regulation through FcRn blocking: a novel mechanism for the treatment of myasthenia gravis J Neurol Sci 2021 430 118074 10.1016/j.jns.2021.118074 34563918 Wolfe GI, Ward ES, de Haard H, Ulrichts P, Mozaffar T, Pasnoor M, et al. IgG regulation through FcRn blocking: a novel mechanism for the treatment of myasthenia gravis. J Neurol Sci. 2021;430: 118074. 34563918 10.1016/j.jns.2021.118074

73. Howard JF Jr Bril V Vu T Karam C Peric S Margania T Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial Lancet Neurol 2021 20 7 526 536 10.1016/S1474-4422(21)00159-9 34146511 Howard JF Jr, Bril V, Vu T, Karam C, Peric S, Margania T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021;20(7):526–36. 34146511 10.1016/S1474-4422(21)00159-9

74. Howard JF Jr Vu T Li G Korobko D Smilowski M Liu L Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: a phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+) Neurotherapeutics 2024 21 5 e00378 10.1016/j.neurot.2024.e00378 39227284 PMC11579873 Howard JF Jr, Vu T, Li G, Korobko D, Smilowski M, Liu L, et al. Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: a phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+). Neurotherapeutics. 2024;21(5): e00378. 39227284 10.1016/j.neurot.2024.e00378 PMC11579873

75. Musick K Howard J Li G Vu T Korobko D Smilowski M P276 Long-term safety, and efficacy of subcutaneous Efgartigimod PH20 in patients with generalized myasthenia gravis: interim results of ADAPT-SC+ Neuromuscul Disord 2023 33 S179 10.1016/j.nmd.2023.07.443 Musick K, Howard J, Li G, Vu T, Korobko D, Smilowski M, et al. P276 Long-term safety, and efficacy of subcutaneous Efgartigimod PH20 in patients with generalized myasthenia gravis: interim results of ADAPT-SC+. Neuromuscul Disord. 2023;33:S179.

76. Bril V Druzdz A Grosskreutz J Habib AA Mantegazza R Sacconi S Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study Lancet Neurol 2023 22 5 383 394 10.1016/S1474-4422(23)00077-7 37059507 Bril V, Druzdz A, Grosskreutz J, Habib AA, Mantegazza R, Sacconi S, et al. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study. Lancet Neurol. 2023;22(5):383–94. 37059507 10.1016/S1474-4422(23)00077-7

77. Bril V Benatar M Andersen H Vissing J Brock M Greve B Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial Neurology 2021 96 6 e853 e865 10.1212/WNL.0000000000011108 33219142 PMC8105899 Bril V, Benatar M, Andersen H, Vissing J, Brock M, Greve B, et al. Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial. Neurology. 2021;96(6):e853–65. 33219142 10.1212/WNL.0000000000011108 PMC8105899

78. Li J Wu X Chu T Tan X Wang S Qu R The efficacy and safety of FcRn inhibitors in patients with myasthenia gravis: a systematic review and meta-analysis J Neurol 2024 271 5 2298 2308 10.1007/s00415-024-12247-x 38431900 Li J, Wu X, Chu T, Tan X, Wang S, Qu R, et al. The efficacy and safety of FcRn inhibitors in patients with myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2024;271(5):2298–308. 38431900 10.1007/s00415-024-12247-x

79. Yan C Yue Y Guan Y Bu B Ke Q Duan R Batoclimab vs placebo for generalized myasthenia gravis: a randomized clinical trial JAMA Neurol 2024 81 4 336 345 10.1001/jamaneurol.2024.0044 38436998 PMC10913013 Yan C, Yue Y, Guan Y, Bu B, Ke Q, Duan R, et al. Batoclimab vs placebo for generalized myasthenia gravis: a randomized clinical trial. JAMA Neurol. 2024;81(4):336–45. 38436998 10.1001/jamaneurol.2024.0044 PMC10913013

80. Nowak RJ Breiner A Bril V Allen JA Khan S Levine T Subcutaneous batoclimab in generalized myasthenia gravis: results from a phase 2a trial with an open-label extension Ann Clin Transl Neurol 2024 11 1 194 206 10.1002/acn3.51946 38062618 PMC10791011 Nowak RJ, Breiner A, Bril V, Allen JA, Khan S, Levine T, et al. Subcutaneous batoclimab in generalized myasthenia gravis: results from a phase 2a trial with an open-label extension. Ann Clin Transl Neurol. 2024;11(1):194–206. 38062618 10.1002/acn3.51946 PMC10791011

81. Benatar M Wiendl H Nowak R Zheng Y Macias W Batoclimab as induction and maintenance therapy in patients with myasthenia gravis: rationale and study design of a phase 3 clinical trial BMJ Neurol Open. 2024 6 1 e000536 10.1136/bmjno-2023-000536 38268752 PMC10806862 Benatar M, Wiendl H, Nowak R, Zheng Y, Macias W. Batoclimab as induction and maintenance therapy in patients with myasthenia gravis: rationale and study design of a phase 3 clinical trial. BMJ Neurol Open. 2024;6(1): e000536. 38268752 10.1136/bmjno-2023-000536 PMC10806862

82. Antozzi C Guptill J Bril V Gamez J Meuth SG Nowak RJ Safety and Efficacy of nipocalimab in patients with generalized myasthenia gravis: results from the randomized phase 2 Vivacity-MG Study Neurology 2024 102 2 e207937 10.1212/WNL.0000000000207937 38165333 PMC10962909 Antozzi C, Guptill J, Bril V, Gamez J, Meuth SG, Nowak RJ, et al. Safety and Efficacy of nipocalimab in patients with generalized myasthenia gravis: results from the randomized phase 2 Vivacity-MG Study. Neurology. 2024;102(2): e207937. 38165333 10.1212/WNL.0000000000207937 PMC10962909

83. Rindi LV Zace D Braccialarghe N Massa B Barchi V Iannazzo R Drug-induced progressive multifocal leukoencephalopathy (PML): a systematic review and meta-analysis Drug Saf 2024 47 4 333 354 10.1007/s40264-023-01383-4 38321317 Rindi LV, Zace D, Braccialarghe N, Massa B, Barchi V, Iannazzo R, et al. Drug-induced progressive multifocal leukoencephalopathy (PML): a systematic review and meta-analysis. Drug Saf. 2024;47(4):333–54. 38321317 10.1007/s40264-023-01383-4

84. Clifford DB Ances B Costello C Rosen-Schmidt S Andersson M Parks D Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis Arch Neurol 2011 68 9 1156 1164 10.1001/archneurol.2011.103 21555606 PMC3428054 Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011;68(9):1156–64. 21555606 10.1001/archneurol.2011.103 PMC3428054

85. Ramdas S Della Marina A Ryan MM McWilliam K Klein A Jacquier D Rituximab in juvenile myasthenia gravis-an international cohort study and literature review Eur J Paediatr Neurol 2022 40 5 10 10.1016/j.ejpn.2022.06.009 35835035 Ramdas S, Della Marina A, Ryan MM, McWilliam K, Klein A, Jacquier D, et al. Rituximab in juvenile myasthenia gravis-an international cohort study and literature review. Eur J Paediatr Neurol. 2022;40:5–10. 35835035 10.1016/j.ejpn.2022.06.009

86. Di Stefano V Lupica A Rispoli MG Di Muzio A Brighina F Rodolico C Rituximab in AChR subtype of myasthenia gravis: systematic review J Neurol Neurosurg Psychiatry 2020 91 4 392 395 10.1136/jnnp-2019-322606 32098874 Di Stefano V, Lupica A, Rispoli MG, Di Muzio A, Brighina F, Rodolico C. Rituximab in AChR subtype of myasthenia gravis: systematic review. J Neurol Neurosurg Psychiatry. 2020;91(4):392–5. 32098874 10.1136/jnnp-2019-322606

87. Zhao C Pu M Chen D Shi J Li Z Guo J Effectiveness and safety of rituximab for refractory myasthenia gravis: a systematic review and single-arm meta-analysis Front Neurol 2021 12 736190 10.3389/fneur.2021.736190 34721267 PMC8548630 Zhao C, Pu M, Chen D, Shi J, Li Z, Guo J, et al. Effectiveness and safety of rituximab for refractory myasthenia gravis: a systematic review and single-arm meta-analysis. Front Neurol. 2021;12: 736190. 34721267 10.3389/fneur.2021.736190 PMC8548630

88. Brauner S Eriksson-Dufva A Hietala MA Frisell T Press R Piehl F Comparison between rituximab treatment for new-onset generalized myasthenia gravis and refractory generalized myasthenia gravis JAMA Neurol 2020 77 8 974 981 10.1001/jamaneurol.2020.0851 32364568 PMC7199182 Brauner S, Eriksson-Dufva A, Hietala MA, Frisell T, Press R, Piehl F. Comparison between rituximab treatment for new-onset generalized myasthenia gravis and refractory generalized myasthenia gravis. JAMA Neurol. 2020;77(8):974–81. 32364568 10.1001/jamaneurol.2020.0851 PMC7199182

89. Russell A Yaraskavitch M Fok D Chhibber S Street L Korngut L Obinutuzumab plus chlorambucil in a patient with severe myasthenia gravis and chronic lymphocytic leukemia J Neuromuscul Dis. 2017 4 3 251 257 10.3233/JND-170211 28869483 Russell A, Yaraskavitch M, Fok D, Chhibber S, Street L, Korngut L. Obinutuzumab plus chlorambucil in a patient with severe myasthenia gravis and chronic lymphocytic leukemia. J Neuromuscul Dis. 2017;4(3):251–7. 28869483 10.3233/JND-170211

90. Waters MJ Field D Ravindran J Refractory myasthenia gravis successfully treated with ofatumumab Muscle Nerve 2019 60 6 E45 E47 10.1002/mus.26707 31509254 Waters MJ, Field D, Ravindran J. Refractory myasthenia gravis successfully treated with ofatumumab. Muscle Nerve. 2019;60(6):E45–7. 31509254 10.1002/mus.26707

91. Scheibe F Ostendorf L Reincke SM Pruss H von Brunneck AC Kohnlein M Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis J Neurol 2020 267 2 317 323 10.1007/s00415-019-09585-6 31630242 Scheibe F, Ostendorf L, Reincke SM, Pruss H, von Brunneck AC, Kohnlein M, et al. Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis. J Neurol. 2020;267(2):317–23. 31630242 10.1007/s00415-019-09585-6

92. Ostendorf L Burns M Durek P Heinz GA Heinrich F Garantziotis P Targeting CD38 with daratumumab in refractory systemic lupus erythematosus N Engl J Med 2020 383 12 1149 1155 10.1056/NEJMoa2023325 32937047 Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020;383(12):1149–55. 32937047 10.1056/NEJMoa2023325

93. Scheibe F Ostendorf L Pruss H Radbruch H Aschman T Hoffmann S Daratumumab for treatment-refractory antibody-mediated diseases in neurology Eur J Neurol 2022 29 6 1847 1854 10.1111/ene.15266 35098616 Scheibe F, Ostendorf L, Pruss H, Radbruch H, Aschman T, Hoffmann S, et al. Daratumumab for treatment-refractory antibody-mediated diseases in neurology. Eur J Neurol. 2022;29(6):1847–54. 35098616 10.1111/ene.15266

94. McDonnell SRP Nguyen VA Walton NM Merkwirth C Hong F Berg D Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease Lupus Sci Med. 2024 11 1 10.1136/lupus-2023-001112 PMC10921479 38453421 McDonnell SRP, Nguyen VA, Walton NM, Merkwirth C, Hong F, Berg D, et al. Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease. Lupus Sci Med. 2024;11:1. 10.1136/lupus-2023-001112 PMC10921479 38453421

95. Moreau P Pylypenko H Grosicki S Karamanesht I Leleu X Grishunina M Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study Lancet Oncol 2011 12 5 431 440 10.1016/S1470-2045(11)70081-X 21507715 Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431–40. 21507715 10.1016/S1470-2045(11)70081-X

96. Khalesi N Korani S Korani M Johnston TP Sahebkar A Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases Inflammopharmacology 2021 29 5 1291 1306 10.1007/s10787-021-00863-2 34424482 Khalesi N, Korani S, Korani M, Johnston TP, Sahebkar A. Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases. Inflammopharmacology. 2021;29(5):1291–306. 34424482 10.1007/s10787-021-00863-2

97. Gomez AM Willcox N Vrolix K Hummel J Nogales-Gadea G Saxena A Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients J Immunol 2014 193 3 1055 1063 10.4049/jimmunol.1301555 24973445 PMC4143753 Gomez AM, Willcox N, Vrolix K, Hummel J, Nogales-Gadea G, Saxena A, et al. Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients. J Immunol. 2014;193(3):1055–63. 24973445 10.4049/jimmunol.1301555 PMC4143753

98. Schneider-Gold C Reinacher-Schick A Ellrichmann G Gold R Bortezomib in severe MuSK-antibody positive myasthenia gravis: first clinical experience Ther Adv Neurol Disord 2017 10 10 339 341 10.1177/1756285617721093 28966662 PMC5607927 Schneider-Gold C, Reinacher-Schick A, Ellrichmann G, Gold R. Bortezomib in severe MuSK-antibody positive myasthenia gravis: first clinical experience. Ther Adv Neurol Disord. 2017;10(10):339–41. 28966662 10.1177/1756285617721093 PMC5607927

99. Sakano S Matsuyama H Ishikawa H Shindo A Ii Y Matsuura K Myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies during therapy for multiple myeloma: a case report BMC Neurol 2020 20 1 240 10.1186/s12883-020-01813-1 32532281 PMC7291755 Sakano S, Matsuyama H, Ishikawa H, Shindo A, Ii Y, Matsuura K, et al. Myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies during therapy for multiple myeloma: a case report. BMC Neurol. 2020;20(1):240. 32532281 10.1186/s12883-020-01813-1 PMC7291755

100. Kohler S Marschenz S Grittner U Alexander T Hiepe F Meisel A Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial BMJ Open 2019 9 1 e024523 10.1136/bmjopen-2018-024523 30696682 PMC6352837 Kohler S, Marschenz S, Grittner U, Alexander T, Hiepe F, Meisel A. Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial. BMJ Open. 2019;9(1): e024523. 30696682 10.1136/bmjopen-2018-024523 PMC6352837

101. Kumpfel T Giglhuber K Aktas O Ayzenberg I Bellmann-Strobl J Haussler V Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD)—Revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management J Neurol 2024 271 1 141 176 10.1007/s00415-023-11910-z 37676297 PMC10770020 Kumpfel T, Giglhuber K, Aktas O, Ayzenberg I, Bellmann-Strobl J, Haussler V, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD)—Revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management. J Neurol. 2024;271(1):141–76. 37676297 10.1007/s00415-023-11910-z PMC10770020

102. Frampton JE Inebilizumab: first approval Drugs 2020 80 12 1259 1264 10.1007/s40265-020-01370-4 32729016 PMC7387876 Frampton JE. Inebilizumab: first approval. Drugs. 2020;80(12):1259–64. 32729016 10.1007/s40265-020-01370-4 PMC7387876

103. Cree BAC Bennett JL Kim HJ Weinshenker BG Pittock SJ Wingerchuk DM Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial Lancet 2019 394 10206 1352 1363 10.1016/S0140-6736(19)31817-3 31495497 Cree BAC, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352–63. 31495497 10.1016/S0140-6736(19)31817-3

104. Schneider P The role of APRIL and BAFF in lymphocyte activation Curr Opin Immunol 2005 17 3 282 289 10.1016/j.coi.2005.04.005 15886118 Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol. 2005;17(3):282–9. 15886118 10.1016/j.coi.2005.04.005

105. Stohl W Hilbert DM The discovery and development of belimumab: the anti-BLyS-lupus connection Nat Biotechnol 2012 30 1 69 77 10.1038/nbt.2076 22231104 PMC3264947 Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol. 2012;30(1):69–77. 22231104 10.1038/nbt.2076 PMC3264947

106. Baker KP Edwards BM Main SH Choi GH Wager RE Halpern WG Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator Arthritis Rheum 2003 48 11 3253 3265 10.1002/art.11299 14613291 Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48(11):3253–65. 14613291 10.1002/art.11299

107. Furie R Petri M Zamani O Cervera R Wallace DJ Tegzova D A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus Arthritis Rheum 2011 63 12 3918 3930 10.1002/art.30613 22127708 PMC5007058 Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918–30. 22127708 10.1002/art.30613 PMC5007058

108. Chan J Walters GD Puri P Jiang SH Safety and efficacy of biological agents in the treatment of systemic lupus erythematosus (SLE) BMC Rheumatol. 2023 7 1 37 10.1186/s41927-023-00358-3 37807057 PMC10561476 Chan J, Walters GD, Puri P, Jiang SH. Safety and efficacy of biological agents in the treatment of systemic lupus erythematosus (SLE). BMC Rheumatol. 2023;7(1):37. 37807057 10.1186/s41927-023-00358-3 PMC10561476

109. Hewett K Sanders DB Grove RA Broderick CL Rudo TJ Bassiri A Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis Neurology 2018 90 16 e1425 e1434 10.1212/WNL.0000000000005323 29661905 PMC5902787 Hewett K, Sanders DB, Grove RA, Broderick CL, Rudo TJ, Bassiri A, et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology. 2018;90(16):e1425–34. 29661905 10.1212/WNL.0000000000005323 PMC5902787

110. Dhillon S Telitacicept: first approval Drugs 2021 81 14 1671 1675 10.1007/s40265-021-01591-1 34463932 Dhillon S. Telitacicept: first approval. Drugs. 2021;81(14):1671–5. 34463932 10.1007/s40265-021-01591-1

111. Yin J Zhao M Xu X Zhang M Xu Z Li Z A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis Eur J Neurol 2024 31 8 e16322 10.1111/ene.16322 38726639 PMC11235933 Yin J, Zhao M, Xu X, Zhang M, Xu Z, Li Z, et al. A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis. Eur J Neurol. 2024;31(8): e16322. 38726639 10.1111/ene.16322 PMC11235933

112. Reich DS Arnold DL Vermersch P Bar-Or A Fox RJ Matta A Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial Lancet Neurol 2021 20 9 729 738 10.1016/S1474-4422(21)00237-4 34418400 PMC8434816 Reich DS, Arnold DL, Vermersch P, Bar-Or A, Fox RJ, Matta A, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021;20(9):729–38. 34418400 10.1016/S1474-4422(21)00237-4 PMC8434816

113. Mendes-Bastos P Brasileiro A Kolkhir P Frischbutter S Scheffel J Monino-Romero S Bruton's tyrosine kinase inhibition-An emerging therapeutic strategy in immune-mediated dermatological conditions Allergy 2022 77 8 2355 2366 10.1111/all.15261 35175630 PMC9545595 Mendes-Bastos P, Brasileiro A, Kolkhir P, Frischbutter S, Scheffel J, Monino-Romero S, et al. Bruton’s tyrosine kinase inhibition-An emerging therapeutic strategy in immune-mediated dermatological conditions. Allergy. 2022;77(8):2355–66. 35175630 10.1111/all.15261 PMC9545595

114. Chen H Qiu Y Yin Z Wang Z Tang Y Ni H Efficacy and safety of the innovative monoclonal antibodies in adults with generalized myasthenia gravis: a Bayesian network analysis Front Immunol 2023 14 1280226 10.3389/fimmu.2023.1280226 38022544 PMC10663412 Chen H, Qiu Y, Yin Z, Wang Z, Tang Y, Ni H, et al. Efficacy and safety of the innovative monoclonal antibodies in adults with generalized myasthenia gravis: a Bayesian network analysis. Front Immunol. 2023;14:1280226. 38022544 10.3389/fimmu.2023.1280226 PMC10663412

115. Giovannoni G Comi G Cook S Rammohan K Rieckmann P Soelberg Sorensen P A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis N Engl J Med 2010 362 5 416 426 10.1056/NEJMoa0902533 20089960 Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–26. 20089960 10.1056/NEJMoa0902533

116. Rejdak K Stelmasiak Z Grieb P Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study Mult Scler Relat Disord. 2019 27 117 120 10.1016/j.msard.2018.10.006 30368223 Rejdak K, Stelmasiak Z, Grieb P. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019;27:117–20. 30368223 10.1016/j.msard.2018.10.006

117. Rejdak K Szklener S Korchut A Baranowski D Cladribine in myasthenia gravis: a pilot open-label study Eur J Neurol 2020 27 3 586 589 10.1111/ene.14124 31705552 Rejdak K, Szklener S, Korchut A, Baranowski D. Cladribine in myasthenia gravis: a pilot open-label study. Eur J Neurol. 2020;27(3):586–9. 31705552 10.1111/ene.14124

118. Laureys G De Bleecker JL Cladribine in myasthenia gravis: a case urging for prudence Muscle Nerve 2019 59 5 E38 10.1002/mus.26446 30758837 Laureys G, De Bleecker JL. Cladribine in myasthenia gravis: a case urging for prudence. Muscle Nerve. 2019;59(5):E38. 30758837 10.1002/mus.26446

119. Ristov J Espie P Ulrich P Sickert D Flandre T Dimitrova M Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody Am J Transplant 2018 18 12 2895 2904 10.1111/ajt.14872 29665205 Ristov J, Espie P, Ulrich P, Sickert D, Flandre T, Dimitrova M, et al. Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody. Am J Transplant. 2018;18(12):2895–904. 29665205 10.1111/ajt.14872

120. GomezMancilla B Meriggioli MN Genge A Roubenoff R Espie P Dupuy C Efficacy and safety of iscalimab, a novel anti-CD40 monoclonal antibody, in moderate-to-severe myasthenia gravis: a phase 2 randomized study J Clin Neurosci 2024 119 76 84 10.1016/j.jocn.2023.11.013 37988976 GomezMancilla B, Meriggioli MN, Genge A, Roubenoff R, Espie P, Dupuy C, et al. Efficacy and safety of iscalimab, a novel anti-CD40 monoclonal antibody, in moderate-to-severe myasthenia gravis: a phase 2 randomized study. J Clin Neurosci. 2024;119:76–84. 37988976 10.1016/j.jocn.2023.11.013

121. Meher BR Mohanty RR Dash A Review of satralizumab for neuromyelitis optica spectrum disorder: a new biologic agent targeting the interleukin-6 receptor Cureus. 2024 16 2 e55100 38558672 10.7759/cureus.55100 PMC10978816 Meher BR, Mohanty RR, Dash A. Review of satralizumab for neuromyelitis optica spectrum disorder: a new biologic agent targeting the interleukin-6 receptor. Cureus. 2024;16(2): e55100. 38558672 10.7759/cureus.55100 PMC10978816

122. Garbers C Heink S Korn T Rose-John S Interleukin-6: designing specific therapeutics for a complex cytokine Nat Rev Drug Discov 2018 17 6 395 412 10.1038/nrd.2018.45 29725131 Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17(6):395–412. 29725131 10.1038/nrd.2018.45

123. Uzawa A Akamine H Kojima Y Ozawa Y Yasuda M Onishi Y High levels of serum interleukin-6 are associated with disease activity in myasthenia gravis J Neuroimmunol 2021 358 577634 10.1016/j.jneuroim.2021.577634 34174586 Uzawa A, Akamine H, Kojima Y, Ozawa Y, Yasuda M, Onishi Y, et al. High levels of serum interleukin-6 are associated with disease activity in myasthenia gravis. J Neuroimmunol. 2021;358: 577634. 34174586 10.1016/j.jneuroim.2021.577634

124. Yang TT Wang ZY Fan ZX Yuan BY Ma L Lu JF A pilot study on tocilizumab in very-late-onset myasthenia gravis J Inflamm Res 2023 16 5835 5843 10.2147/JIR.S423098 38088944 PMC10714969 Yang TT, Wang ZY, Fan ZX, Yuan BY, Ma L, Lu JF, et al. A pilot study on tocilizumab in very-late-onset myasthenia gravis. J Inflamm Res. 2023;16:5835–43. 38088944 10.2147/JIR.S423098 PMC10714969

125. Jia D Zhang F Li H Shen Y Jin Z Shi FD Responsiveness to tocilizumab in anti-acetylcholine receptor-positive generalized myasthenia gravis Aging Dis 2024 15 2 824 830 10.14336/AD.2023.0528 37450932 PMC10917550 Jia D, Zhang F, Li H, Shen Y, Jin Z, Shi FD, et al. Responsiveness to tocilizumab in anti-acetylcholine receptor-positive generalized myasthenia gravis. Aging Dis. 2024;15(2):824–30. 37450932 10.14336/AD.2023.0528 PMC10917550

126. Ruan Z Tang Y Gao T Li C Guo R Sun C Efficacy and safety of tocilizumab in patients with refractory generalized myasthenia gravis CNS Neurosci Ther 2024 30 6 e14793 10.1111/cns.14793 38894580 PMC11187874 Ruan Z, Tang Y, Gao T, Li C, Guo R, Sun C, et al. Efficacy and safety of tocilizumab in patients with refractory generalized myasthenia gravis. CNS Neurosci Ther. 2024;30(6): e14793. 38894580 10.1111/cns.14793 PMC11187874

127. Mariottini A Bulgarini G Cornacchini S Damato V Saccardi R Massacesi L Hematopoietic stem cell transplantation for the treatment of autoimmune neurological diseases: an update Bioengineering (Basel). 2023 10 2 10.3390/bioengineering10020176 PMC9952685 36829670 Mariottini A, Bulgarini G, Cornacchini S, Damato V, Saccardi R, Massacesi L. Hematopoietic stem cell transplantation for the treatment of autoimmune neurological diseases: an update. Bioengineering (Basel). 2023;10:2. 10.3390/bioengineering10020176 PMC9952685 36829670

128. Hakansson I Sandstedt A Lundin F Askmark H Pirskanen R Carlson K Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis—a case report Neuromuscul Disord 2017 27 1 90 93 10.1016/j.nmd.2016.09.020 27863874 Hakansson I, Sandstedt A, Lundin F, Askmark H, Pirskanen R, Carlson K, et al. Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis—a case report. Neuromuscul Disord. 2017;27(1):90–3. 27863874 10.1016/j.nmd.2016.09.020

129. Bryant A Atkins H Pringle CE Allan D Anstee G Bence-Bruckler I Myasthenia gravis treated with autologous hematopoietic stem cell transplantation JAMA Neurol 2016 73 6 652 658 10.1001/jamaneurol.2016.0113 27043206 Bryant A, Atkins H, Pringle CE, Allan D, Anstee G, Bence-Bruckler I, et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. 2016;73(6):652–8. 27043206 10.1001/jamaneurol.2016.0113

130. Sossa Melo CL Pena AM Salazar LA Jimenez SI Gomez ED Chalela CM Autologous hematopoietic stem cell transplantation in a patient with refractory seropositive myasthenia gravis: a case report Neuromuscul Disord 2019 29 2 142 145 10.1016/j.nmd.2018.11.008 30639064 Sossa Melo CL, Pena AM, Salazar LA, Jimenez SI, Gomez ED, Chalela CM, et al. Autologous hematopoietic stem cell transplantation in a patient with refractory seropositive myasthenia gravis: a case report. Neuromuscul Disord. 2019;29(2):142–5. 30639064 10.1016/j.nmd.2018.11.008

131. Beland B Hahn C Jamani K Chhibber S White C Atkins H Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies Muscle Nerve 2023 67 2 154 157 10.1002/mus.27772 36527328 Beland B, Hahn C, Jamani K, Chhibber S, White C, Atkins H, et al. Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies. Muscle Nerve. 2023;67(2):154–7. 36527328 10.1002/mus.27772

132. Schlatter MI Yandamuri SS O'Connor KC Nowak RJ Pham MC Obaid AH Remission of severe myasthenia gravis after autologous stem cell transplantation Ann Clin Transl Neurol 2023 10 11 2105 2113 10.1002/acn3.51898 37726935 PMC10646993 Schlatter MI, Yandamuri SS, O’Connor KC, Nowak RJ, Pham MC, Obaid AH, et al. Remission of severe myasthenia gravis after autologous stem cell transplantation. Ann Clin Transl Neurol. 2023;10(11):2105–13. 37726935 10.1002/acn3.51898 PMC10646993

133. Deligny C Clave E Sibon D Daikeler T Keshmandt H Carmagnat M New onset of myasthenia gravis after treatment of systemic sclerosis by autologous hematopoietic stem cell transplantation: sustained autoimmunity or inadequate reset of tolerance? Hum Immunol 2010 71 4 363 365 10.1016/j.humimm.2010.01.013 20085795 Deligny C, Clave E, Sibon D, Daikeler T, Keshmandt H, Carmagnat M, et al. New onset of myasthenia gravis after treatment of systemic sclerosis by autologous hematopoietic stem cell transplantation: sustained autoimmunity or inadequate reset of tolerance? Hum Immunol. 2010;71(4):363–5. 20085795 10.1016/j.humimm.2010.01.013

134. Pecher AC, Hensen L, Lengerke C, Henes J. The future of CAR T therapeutics to treat autoimmune disorders. Mol Diagn Ther. 2024. 10.1007/s40291-024-00730-0 PMC11349844 39078456

135. Granit V Benatar M Kurtoglu M Miljkovic MD Chahin N Sahagian G Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study Lancet Neurol 2023 22 7 578 590 10.1016/S1474-4422(23)00194-1 37353278 PMC10416207 Granit V, Benatar M, Kurtoglu M, Miljkovic MD, Chahin N, Sahagian G, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol. 2023;22(7):578–90. 37353278 10.1016/S1474-4422(23)00194-1 PMC10416207

136. Haghikia A Hegelmaier T Wolleschak D Bottcher M Desel C Borie D Anti-CD19 CAR T cells for refractory myasthenia gravis Lancet Neurol 2023 22 12 1104 1105 10.1016/S1474-4422(23)00375-7 37977704 Haghikia A, Hegelmaier T, Wolleschak D, Bottcher M, Desel C, Borie D, et al. Anti-CD19 CAR T cells for refractory myasthenia gravis. Lancet Neurol. 2023;22(12):1104–5. 37977704 10.1016/S1474-4422(23)00375-7

137. Motte J Sgodzai M Schneider-Gold C Steckel N Mika T Hegelmaier T Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells Neuron 2024 112 11 1757 1763 10.1016/j.neuron.2024.04.014 38697115 Motte J, Sgodzai M, Schneider-Gold C, Steckel N, Mika T, Hegelmaier T, et al. Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells. Neuron. 2024;112(11):1757–63. 38697115 10.1016/j.neuron.2024.04.014

138. Katyal N Narula N Govindarajan R Clinical experience with eculizumab in treatment-Refractory acetylcholine receptor antibody-positive generalized myasthenia gravis J Neuromuscul Dis. 2021 8 2 287 294 10.3233/JND-200584 33325394 PMC8075396 Katyal N, Narula N, Govindarajan R. Clinical experience with eculizumab in treatment-Refractory acetylcholine receptor antibody-positive generalized myasthenia gravis. J Neuromuscul Dis. 2021;8(2):287–94. 33325394 10.3233/JND-200584 PMC8075396

139. Nishimura JI Kawaguchi T Ito S Murai H Shimono A Matsuda T Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan Int J Hematol 2023 118 4 419 431 10.1007/s12185-023-03630-x 37515657 Nishimura JI, Kawaguchi T, Ito S, Murai H, Shimono A, Matsuda T, et al. Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan. Int J Hematol. 2023;118(4):419–31. 37515657 10.1007/s12185-023-03630-x

140. Pane C Di Stefano V Cuomo N Sarnataro A Vinciguerra C Bevilacqua L A real-life experience with eculizumab and efgartigimod in generalized myasthenia gravis patients J Neurol 2024 271 9 6209 6219 10.1007/s00415-024-12588-7 39080054 PMC11377599 Pane C, Di Stefano V, Cuomo N, Sarnataro A, Vinciguerra C, Bevilacqua L, et al. A real-life experience with eculizumab and efgartigimod in generalized myasthenia gravis patients. J Neurol. 2024;271(9):6209–19. 39080054 10.1007/s00415-024-12588-7 PMC11377599

141. Habib AA, Klink AJ, Muppidi S, Parthan A, Sader SC, Balanean A, et al. United States clinical practice experience with eculizumab in myasthenia gravis: symptoms, function, and immunosuppressant therapy use. J Neurol. 2024. 10.1007/s00415-024-12569-w PMC11377470 39052039

142. Tokuyasu D Suzuki S Uzawa A Nagane Y Masuda M Konno S Real-world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis Ann Clin Transl Neurol 2024 11 5 1338 1346 10.1002/acn3.52051 38572524 PMC11093249 Tokuyasu D, Suzuki S, Uzawa A, Nagane Y, Masuda M, Konno S, et al. Real-world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis. Ann Clin Transl Neurol. 2024;11(5):1338–46. 38572524 10.1002/acn3.52051 PMC11093249

143. Youssef I Abbas MS Manafi A Akhondi H Youssef D Disseminated cryptococcosis post eculizumab therapy: a case report and literature review Cureus. 2024 16 4 e58852 38784297 10.7759/cureus.58852 PMC11115998 Youssef I, Abbas MS, Manafi A, Akhondi H, Youssef D. Disseminated cryptococcosis post eculizumab therapy: a case report and literature review. Cureus. 2024;16(4): e58852. 38784297 10.7759/cureus.58852 PMC11115998

144. Emine Rabia K Omer Faruk T Furkan S Lazrak ES Ozen PA Tuncer A Probable eculizumab-associated hepatotoxicity in a patient with neuromyelitis optica: a case report Int J Neurosci 2023 8 1 5 10.1080/00207454.2023.2253361 37632449 Emine Rabia K, Omer Faruk T, Furkan S, Lazrak ES, Ozen PA, Tuncer A. Probable eculizumab-associated hepatotoxicity in a patient with neuromyelitis optica: a case report. Int J Neurosci. 2023;8:1–5. 10.1080/00207454.2023.2253361 37632449

145. Hayes W Tschumi S Ling SC Feber J Kirschfink M Licht C Eculizumab hepatotoxicity in pediatric aHUS Pediatr Nephrol 2015 30 5 775 781 10.1007/s00467-014-2990-5 25416628 Hayes W, Tschumi S, Ling SC, Feber J, Kirschfink M, Licht C. Eculizumab hepatotoxicity in pediatric aHUS. Pediatr Nephrol. 2015;30(5):775–81. 25416628 10.1007/s00467-014-2990-5

146. Ricciardi D, Erra C, Tuccillo F, De Martino BM, Fasolino A, Habetswallner F. Eculizumab in refractory myasthenia gravis: a real-world single-center experience. Neurol Sci. 2024. 10.1007/s10072-024-07861-6 39495373

147. Song J Huan X Chen Y Luo Y Zhong H Wang Y The safety and efficacy profile of eculizumab in myasthenic crisis: a prospective small case series Ther Adv Neurol Disord 2024 17 17562864241261602 10.1177/17562864241261602 39072008 PMC11282533 Song J, Huan X, Chen Y, Luo Y, Zhong H, Wang Y, et al. The safety and efficacy profile of eculizumab in myasthenic crisis: a prospective small case series. Ther Adv Neurol Disord. 2024;17:17562864241261602. 39072008 10.1177/17562864241261602 PMC11282533

148. Strano CMM Sorrenti B Bosco L Falzone YM Fazio R Filippi M Eculizumab as a fast-acting rescue therapy in a refractory myasthenic crisis: a case report J Neurol 2022 269 11 6152 6154 10.1007/s00415-022-11222-8 35705882 Strano CMM, Sorrenti B, Bosco L, Falzone YM, Fazio R, Filippi M. Eculizumab as a fast-acting rescue therapy in a refractory myasthenic crisis: a case report. J Neurol. 2022;269(11):6152–4. 35705882 10.1007/s00415-022-11222-8

149. Yeo CJJ Pleitez MY Eculizumab in refractory myasthenic crisis Muscle Nerve 2018 58 2 E13 E15 10.1002/mus.26124 29524335 Yeo CJJ, Pleitez MY. Eculizumab in refractory myasthenic crisis. Muscle Nerve. 2018;58(2):E13–5. 29524335 10.1002/mus.26124

150. Quasthoff S Two-decade battle with myasthenia gravis: a breakthrough case report on the long-term success with eculizumab and ravulizumab treatment Clin Case Rep. 2024 12 11 e9547 10.1002/ccr3.9547 39502126 PMC11534635 Quasthoff S. Two-decade battle with myasthenia gravis: a breakthrough case report on the long-term success with eculizumab and ravulizumab treatment. Clin Case Rep. 2024;12(11): e9547. 39502126 10.1002/ccr3.9547 PMC11534635

151. Nelke C Schroeter CB Stascheit F Pawlitzki M Regner-Nelke L Huntemann N Eculizumab versus rituximab in generalised myasthenia gravis J Neurol Neurosurg Psychiatry 2022 93 5 548 554 10.1136/jnnp-2021-328665 35246490 PMC9016243 Nelke C, Schroeter CB, Stascheit F, Pawlitzki M, Regner-Nelke L, Huntemann N, et al. Eculizumab versus rituximab in generalised myasthenia gravis. J Neurol Neurosurg Psychiatry. 2022;93(5):548–54. 35246490 10.1136/jnnp-2021-328665 PMC9016243

152. Schonfelder K Kuhne L Schulte-Kemna L Kaufeld J Rohn H Kribben A Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS- real-world data BMC Nephrol 2024 25 1 202 10.1186/s12882-024-03638-3 38898427 PMC11188157 Schonfelder K, Kuhne L, Schulte-Kemna L, Kaufeld J, Rohn H, Kribben A, et al. Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS- real-world data. BMC Nephrol. 2024;25(1):202. 38898427 10.1186/s12882-024-03638-3 PMC11188157

153. Dixon BP Kavanagh D Aris ADM Adams B Kang HG Wang E Ravulizumab in atypical hemolytic uremic syndrome: an analysis of 2-year efficacy and safety outcomes in 2 phase 3 trials Kidney Med. 2024 6 8 100855 10.1016/j.xkme.2024.100855 39105067 PMC11298908 Dixon BP, Kavanagh D, Aris ADM, Adams B, Kang HG, Wang E, et al. Ravulizumab in atypical hemolytic uremic syndrome: an analysis of 2-year efficacy and safety outcomes in 2 phase 3 trials. Kidney Med. 2024;6(8): 100855. 39105067 10.1016/j.xkme.2024.100855 PMC11298908

154. Chonat S Kulagin A Maschan A Bartels M Buechner J Punzalan R Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria Blood Adv 2024 8 11 2813 2824 10.1182/bloodadvances.2023012267 38551806 PMC11176942 Chonat S, Kulagin A, Maschan A, Bartels M, Buechner J, Punzalan R, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv. 2024;8(11):2813–24. 38551806 10.1182/bloodadvances.2023012267 PMC11176942

155. Mallenahalli Neeekantappa V, Kamath A, Bharathi Rajaduraivelpandian P. Safety profile of monoclonal antibodies and subsequent drug developments in the treatment of paroxysmal nocturnal hemoglobinuria. Medicina (Kaunas). 2024;60(3). 10.3390/medicina60030379 PMC10971871 38541105

156. Katyal N Govindarajan R Goyal N Muley S Muppidi S Ravulizumab use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice Front Neurol 2024 15 1378080 10.3389/fneur.2024.1378080 38919970 PMC11197931 Katyal N, Govindarajan R, Goyal N, Muley S, Muppidi S. Ravulizumab use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice. Front Neurol. 2024;15:1378080. 38919970 10.3389/fneur.2024.1378080 PMC11197931

157. Stascheit F Sousa CDF Aigner A Behrens M Keller CW Klotz L Ravulizumab and efgartigimod in myasthenia gravis: a real-world study Neurol Neuroimmunol Neuroinflamm. 2025 12 1 e200331 10.1212/NXI.0000000000200331 39602677 PMC11604103 Stascheit F, Sousa CDF, Aigner A, Behrens M, Keller CW, Klotz L, et al. Ravulizumab and efgartigimod in myasthenia gravis: a real-world study. Neurol Neuroimmunol Neuroinflamm. 2025;12(1): e200331. 39602677 10.1212/NXI.0000000000200331 PMC11604103

158. Konen FF Jendretzky KF Ratuszny D Schuppner R Suhs KW Pawlitzki M Ravulizumab in myasthenic crisis: the first case report J Neurol 2024 271 5 2898 2901 10.1007/s00415-024-12234-2 38388927 PMC11055754 Konen FF, Jendretzky KF, Ratuszny D, Schuppner R, Suhs KW, Pawlitzki M, et al. Ravulizumab in myasthenic crisis: the first case report. J Neurol. 2024;271(5):2898–901. 38388927 10.1007/s00415-024-12234-2 PMC11055754

159. Howard JF Jr Bril V Vu T Karam C Peric S De Bleecker JL Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis Front Neurol 2023 14 1284444 10.3389/fneur.2023.1284444 38318236 PMC10842202 Howard JF Jr, Bril V, Vu T, Karam C, Peric S, De Bleecker JL, et al. Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis. Front Neurol. 2023;14:1284444. 38318236 10.3389/fneur.2023.1284444 PMC10842202

160. Wang P Zhang B Yin J Xi J Tan Y Gao F Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients Front Neurol 2024 15 1407418 10.3389/fneur.2024.1407418 38966082 PMC11222781 Wang P, Zhang B, Yin J, Xi J, Tan Y, Gao F, et al. Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients. Front Neurol. 2024;15:1407418. 38966082 10.3389/fneur.2024.1407418 PMC11222781

161. Luo S Jiang Q Zeng W Wang Q Zou Z Yu Y Efgartigimod for generalized myasthenia gravis: a multicenter real-world cohort study in China Ann Clin Transl Neurol 2024 11 8 2212 2221 10.1002/acn3.52142 38973109 PMC11330228 Luo S, Jiang Q, Zeng W, Wang Q, Zou Z, Yu Y, et al. Efgartigimod for generalized myasthenia gravis: a multicenter real-world cohort study in China. Ann Clin Transl Neurol. 2024;11(8):2212–21. 38973109 10.1002/acn3.52142 PMC11330228

162. Fuchs L Shelly S Vigiser I Kolb H Regev K Schwartzmann Y Real-world experience with efgartigimod in patients with myasthenia gravis J Neurol 2024 271 6 3462 3470 10.1007/s00415-024-12293-5 38528163 Fuchs L, Shelly S, Vigiser I, Kolb H, Regev K, Schwartzmann Y, et al. Real-world experience with efgartigimod in patients with myasthenia gravis. J Neurol. 2024;271(6):3462–70. 38528163 10.1007/s00415-024-12293-5

163. Konno S, Uchi T, Kihara H, Sugimoto H. Real-world case series of efgartigimod for Japanese generalized myasthenia gravis: well-tailored treatment cycle intervals contribute to sustained symptom control. Biomedicines. 2024;12(6). 10.3390/biomedicines12061214 PMC11200869 38927421

164. Horiuchi K Nakamura S Yamada K Inoue T Oiwa K Retrospective analysis of efgartigimod use in patients with double-seronegative generalized myasthenia gravis: a case series Neuromuscul Disord 2024 39 37 41 10.1016/j.nmd.2024.04.005 38772072 Horiuchi K, Nakamura S, Yamada K, Inoue T, Oiwa K. Retrospective analysis of efgartigimod use in patients with double-seronegative generalized myasthenia gravis: a case series. Neuromuscul Disord. 2024;39:37–41. 38772072 10.1016/j.nmd.2024.04.005

165. Nomura T Imamura M Imura M Mizutani H Ueda M Efgartigimod treatment for generalized myasthenia gravis: a single-center case series of 16 patients Front Neurol 2024 15 1472845 10.3389/fneur.2024.1472845 39469071 PMC11514137 Nomura T, Imamura M, Imura M, Mizutani H, Ueda M. Efgartigimod treatment for generalized myasthenia gravis: a single-center case series of 16 patients. Front Neurol. 2024;15:1472845. 39469071 10.3389/fneur.2024.1472845 PMC11514137

166. Alhaj Omar O Diel NJ Gerner ST Muck A Huttner HB Kramer-Best HH Efgartigimod as rescue medication in a patient with therapy-refractory myasthenic crisis Case Rep Neurol Med. 2024 2024 9455237 38939234 10.1155/2024/9455237 PMC11211016 Alhaj Omar O, Diel NJ, Gerner ST, Muck A, Huttner HB, Kramer-Best HH. Efgartigimod as rescue medication in a patient with therapy-refractory myasthenic crisis. Case Rep Neurol Med. 2024;2024:9455237. 38939234 10.1155/2024/9455237 PMC11211016

167. Song J Wang H Huan X Jiang Q Wu Z Yan C Efgartigimod as a promising add-on therapy for myasthenic crisis: a prospective case series Front Immunol 2024 15 1418503 10.3389/fimmu.2024.1418503 39136012 PMC11317420 Song J, Wang H, Huan X, Jiang Q, Wu Z, Yan C, et al. Efgartigimod as a promising add-on therapy for myasthenic crisis: a prospective case series. Front Immunol. 2024;15:1418503. 39136012 10.3389/fimmu.2024.1418503 PMC11317420

168. Ohara H Kikutsuji N Iguchi N Kinoshita M Efgartigimod combined with steroids as a fast-acting therapy for myasthenic crisis: a case report BMC Neurol 2024 24 1 292 10.1186/s12883-024-03804-y 39174898 PMC11340165 Ohara H, Kikutsuji N, Iguchi N, Kinoshita M. Efgartigimod combined with steroids as a fast-acting therapy for myasthenic crisis: a case report. BMC Neurol. 2024;24(1):292. 39174898 10.1186/s12883-024-03804-y PMC11340165

169. Hong Y Gao L Huang SQ Liu S Feng S Chen YB Efgartigimod as a fast-acting add-on therapy in manifest and impending myasthenic crisis: a single-center case series J Neuroimmunol 2024 395 578431 10.1016/j.jneuroim.2024.578431 39142025 Hong Y, Gao L, Huang SQ, Liu S, Feng S, Chen YB, et al. Efgartigimod as a fast-acting add-on therapy in manifest and impending myasthenic crisis: a single-center case series. J Neuroimmunol. 2024;395: 578431. 39142025 10.1016/j.jneuroim.2024.578431

170. Tanaka K, Yoshikawa M, Inoue Y, Tsumura K, Hoshino Y, Shichijo C, et al. Efgartigimod successfully ameliorated acute exacerbation of myasthenia gravis with anti-muscle-specific kinase antibodies. Intern Med. 2024;advpub. 10.2169/internalmedicine.3726-24 PMC11986312 39111891

171. Ma J Zhang H Zhao J Su M Feng Y Yuan X Efgartigimod versus intravenous immunoglobulin in the treatment of patients with impending myasthenic crisis Sci Rep 2024 14 1 28394 10.1038/s41598-024-79918-7 39551862 PMC11570634 Ma J, Zhang H, Zhao J, Su M, Feng Y, Yuan X, et al. Efgartigimod versus intravenous immunoglobulin in the treatment of patients with impending myasthenic crisis. Sci Rep. 2024;14(1):28394. 39551862 10.1038/s41598-024-79918-7 PMC11570634

172. van Steen C Celico L Spaepen E Hagenacker T Meuth SG Ruck T Efgartigimod and ravulizumab for treating acetylcholine receptor auto-antibody-positive (AChR-Ab+) generalized myasthenia gravis: indirect treatment comparison Adv Ther 2024 41 6 2486 2499 10.1007/s12325-024-02856-3 38642198 PMC11133097 van Steen C, Celico L, Spaepen E, Hagenacker T, Meuth SG, Ruck T, et al. Efgartigimod and ravulizumab for treating acetylcholine receptor auto-antibody-positive (AChR-Ab+) generalized myasthenia gravis: indirect treatment comparison. Adv Ther. 2024;41(6):2486–99. 38642198 10.1007/s12325-024-02856-3 PMC11133097

173. Sacca F Pane C Espinosa PE Sormani MP Signori A Efficacy of innovative therapies in myasthenia gravis: a systematic review, meta-analysis and network meta-analysis Eur J Neurol 2023 30 12 3854 3867 10.1111/ene.15872 37204031 Sacca F, Pane C, Espinosa PE, Sormani MP, Signori A. Efficacy of innovative therapies in myasthenia gravis: a systematic review, meta-analysis and network meta-analysis. Eur J Neurol. 2023;30(12):3854–67. 37204031 10.1111/ene.15872

174. Ma Y Nie X Zhu G Qi W Hao L Guo X The efficacy and safety of different targeted drugs for the treatment of generalized myasthenia gravis: a systematic review and Bayesian network meta-analysis CNS Drugs 2024 38 2 93 104 10.1007/s40263-024-01062-7 38300476 Ma Y, Nie X, Zhu G, Qi W, Hao L, Guo X. The efficacy and safety of different targeted drugs for the treatment of generalized myasthenia gravis: a systematic review and Bayesian network meta-analysis. CNS Drugs. 2024;38(2):93–104. 38300476 10.1007/s40263-024-01062-7

175. Smith AG Wolfe GI Habib AA Qi CZ Yang H Du M Risk-benefit analysis of novel treatments for patients with generalized myasthenia gravis Adv Ther 2024 41 12 4628 4647 10.1007/s12325-024-03014-5 39470879 PMC11550228 Smith AG, Wolfe GI, Habib AA, Qi CZ, Yang H, Du M, et al. Risk-benefit analysis of novel treatments for patients with generalized myasthenia gravis. Adv Ther. 2024;41(12):4628–47. 39470879 10.1007/s12325-024-03014-5 PMC11550228

176. Mao ZF Mo XA Qin C Lai YR Olde Hartman TC Course and prognosis of myasthenia gravis: a systematic review Eur J Neurol 2010 17 7 913 921 10.1111/j.1468-1331.2010.03017.x 20402761 Mao ZF, Mo XA, Qin C, Lai YR, Olde Hartman TC. Course and prognosis of myasthenia gravis: a systematic review. Eur J Neurol. 2010;17(7):913–21. 20402761 10.1111/j.1468-1331.2010.03017.x