The New Therapeutic Era in Autoimmune Neuromuscular Disease

For decades, clinicians caring for patients with autoimmune neuromuscular disorders relied on symptomatic treatment and broadly acting immunosuppressive therapies, many used off-label, with variable efficacy, slow onset and substantial toxicity. In gMG, treatment has included pyridostigmine, corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, intravenous immunoglobulin (IVIg), plasma exchange, thymectomy and, in selected patients, rituximab. These therapies remain important. However, the emergence of targeted therapies, including FcRn inhibitors and terminal complement inhibitors, has altered the treatment landscape for patients with refractory or highly symptomatic disease. ^{Reference Gerischer, Doksani, Hoffmann and Meisel1}

Canada’s Drug Agency (CDA) has issued positive reimbursement recommendations with conditions for several targeted therapies in gMG. These advances should be a success story. Instead, in Canada, they risk becoming a case study in inequitable access. This issue is increasingly urgent because targeted therapies are becoming part of the expected therapeutic landscape rather than exceptional one-off interventions.

When Reimbursement Criteria Override Clinical Evidence

Access to targeted therapies for gMG is not determined solely by Health Canada approval or the CDA national health technology assessment (HTA) recommendations. Final public reimbursement remains provincial, and provincial criteria may impose additional requirements that differ from national recommendations and from one another. In some jurisdictions, access to targeted therapies may require documentation that a patient is refractory to, intolerant of, or unable to receive rituximab before public coverage is granted.

This is difficult to reconcile with the principles of evidence-based prescribing. Rituximab has an important role in selected patients with gMG, particularly muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG); however, the evidence base in AChR antibody-positive gMG is less compelling, and the biologic rationale is weaker. Mechanistically, rituximab targets CD20-expressing B-cells, but not long-lived plasma cells, which have lost CD20 expression and are thought to be a major source of ongoing AChR antibody production. In contrast, MuSK-MG may be more dependent on short-lived antibody-producing cells and plasmablast-lineage activity, providing a stronger biologic rationale for B-cell depletion.

Before 2022, evidence supporting rituximab in AChR-positive disease came largely from case series and mixed MuSK/AChR cohorts, and rituximab was generally considered an adjunctive option for refractory disease. ^{Reference Gerischer, Doksani, Hoffmann and Meisel1} In 2022, the BeatMG phase 2 randomized controlled trial did not demonstrate a steroid-sparing benefit over placebo, its primary outcome, in patients with AChR-positive gMG, and concluded that a successful phase 3 study of rituximab in this population was unlikely. Subsequently, the small phase 3 RINOMAX trial, which enrolled patients with onset of generalized symptoms 12 months or less before inclusion, showed a positive primary outcome, with more patients achieving minimal manifestation status at 16 weeks after early treatment with a single low dose of rituximab 500 mg. ^{Reference Piehl, Eriksson-Dufva and Budzianowska2} However, key secondary outcomes, including Myasthenia Gravis Activities of Daily Living (MG-ADL), did not show statistically or clinically meaningful benefit, and interpretation is limited by the small sample size and baseline group imbalances, including disease severity and steroid use. Taken together, this evidence may support rituximab as a reasonable clinical option in selected patients, but it does not justify making rituximab failure a mandatory prerequisite before accessing targeted therapies in patients further along in their disease course. Moreover, in a systematic review, meta-analysis and network meta-analysis of biologic therapies in myasthenia gravis, rituximab was not associated with statistically significant improvement in MG-ADL or Quantitative Myasthenia Gravis scores compared with placebo, whereas FcRn inhibition demonstrated favorable comparative efficacy across key clinical outcomes. ^{Reference Saccà, Pane, Espinosa, Sormani and Signori3}

The argument is not that rituximab is inappropriate for AChR antibody-positive gMG. Rather, the problem is that reimbursement policy can transform a clinician-selected, individualized, off-label option into a mandatory administrative gatekeeper. These are not the same thing. A neurologist choosing rituximab for a specific patient based on disease phenotype, antibody status, comorbidity, prior treatment response, safety considerations and patient preference is practicing individualized medicine. A reimbursement rule requiring rituximab failure before access to a targeted, nationally reviewed therapy is practicing administrative sequencing.

This distinction is particularly important because targeted therapies in gMG are not interchangeable. FcRn inhibitors and complement inhibitors differ in mechanism, onset, administration, adverse effect profile, monitoring requirements, vaccination considerations and suitability for individual patients. A rigid fail-first pathway does not reflect this clinical nuance.

The Cost Argument and Its Limits

Fail-first policies are often justified on economic grounds, and the costs of targeted therapies are substantial. Canadian and international HTA processes have consistently found that complement inhibitors and FcRn inhibitors exceed conventional willingness-to-pay thresholds when compared with conventional therapy alone. Public drug plans must make difficult decisions, and health-care sustainability is a legitimate concern.

However, cost containment should not require clinicians to prescribe around policy rather than disease biology. Nor should it require patients to experience ongoing disability, prolonged corticosteroid exposure, avoidable rescue therapy or clinical deterioration before accessing a therapy that has already undergone national HTA.

The economic burden of inadequately controlled gMG is considerable. Patients who remain symptomatic despite conventional immunosuppression may require high-dose corticosteroids with their attendant chronic complications, multiple nonsteroidal immunosuppressive agents, intermittent plasma exchange, chronic IVIg, recurrent emergency department visits and hospitalization.

For some patients already receiving chronic IVIg, the economic calculus may favor targeted therapy directly. A Canadian cost-effectiveness analysis favored the FcRn inhibitor efgartigimod over chronic immunoglobulin from a Canadian public-payer perspective, yielding an estimated 3.45 additional quality-adjusted life-years and ＄257,020 in cost savings over a lifetime horizon. ^{Reference Siddiqi, Qi and Zhou4} This finding does not apply to all patients with gMG, nor does it eliminate the need for careful stewardship. However, it illustrates that policies delaying access to targeted therapies may be economically counterproductive for a meaningful subset of patients. Policies that appear to reduce drug spending may simply shift costs elsewhere, including rescue therapies, hospitalizations, emergency care, lost productivity and cumulative treatment toxicity. In doing so, they may prioritize short-term pharmaceutical expenditure over the broader lifetime cost of uncontrolled disease.

The Equity Argument

A national HTA process is intended to promote consistency, transparency and evidence-informed decision-making. Yet final access remains provincial. The result is a patchwork in which two patients with the same disease, same antibody status, same disability and same specialist recommendation may face different treatment pathways depending on postal code.

This fragmentation compounds existing vulnerability, including health literacy, caregiver support, ability to travel for specialist care, time off work and capacity to navigate prolonged appeal processes. The Canadian BIND study, which included individuals with inherited and acquired neuromuscular disorders, found that 73% of adults with neuromuscular diseases experience significant financial toxicity, with scores comparable to those of patients with stage IV cancer. Only 20% of participants were employed, compared with 61% of the general Canadian population, and limited earning potential further reduces access to private insurance and necessary treatment. ^{Reference Grant, Smith and Lessard5} Administrative barriers to approved therapies deepen these inequities.

The issue is not simply whether one therapy is available in one province. The broader concern is that Canadian patients with the same neuromuscular disease may encounter different definitions of “eligible,” different administrative hurdles, different required treatment failures and different timelines for access. This is difficult to defend clinically and ethically.

The Clinical Harms of Fail-First Policies

A growing body of evidence demonstrates the clinical consequences of administrative treatment barriers. A scoping review in JAMA Neurology found that 60% of prior authorization encounters result in care delays and 25% are associated with increased disease activity across neurologic conditions. ^{Reference Gotlieb, Joseph, Blank and Jetté6} In multiple sclerosis, initial claim denial delayed approval substantially compared with initial approval, and approximately half of patients with access barriers experienced relapses. ^{Reference Gotlieb, Joseph, Blank and Jetté6}

Treatment sequencing should account not only for mechanism and safety but also for the urgency of disease control and expected time to clinical response. Clinical benefit from rituximab may take several months to emerge, whereas FcRn inhibitors and complement inhibitors can produce clinically meaningful improvement within days to weeks. For patients with persistent bulbar or respiratory weakness, requiring rituximab failure before access to a more rapidly acting targeted therapy may prolong disability, disrupt employment or education, increase reliance on rescue therapies such as IVIg or plasma exchange and increase the risk of myasthenic crisis, hospitalization or prolonged corticosteroid exposure. A growing body of evidence further suggests that early disease control influences the subsequent likelihood of achieving treatment goals such as minimal manifestations or minimal symptom expression status. ^{Reference Narayanaswami, Mantegazza and Barnett-Tapia7} For a patient with high symptom burden who does not respond to rituximab and is later escalated to a targeted therapy, months spent satisfying a fail-first requirement may represent a lost early therapeutic window rather than a neutral delay. Therefore, when reimbursement policies mandate failure of a slower-acting off-label therapy before access to an approved targeted agent, they may inadvertently expose patients to avoidable morbidity.

Rituximab also carries its own risks, including infusion reactions, prolonged B-cell depletion, hypogammaglobulinemia and infection risk. These risks may be appropriate when rituximab is selected clinically, but they are harder to defend when imposed administratively. Modern neuromuscular care increasingly emphasizes shared decision-making, in which treatment selection reflects disease characteristics, patient goals, route of administration, risk tolerance, family circumstances and lifestyle. Mandatory sequencing policies replace these individualized discussions with administrative requirements that may not align with patient preferences or clinical priorities. Requiring failure of an off-label therapy before access to a disease-specific, nationally reviewed and Health Canada-approved treatment is distinct from a clinician choosing that same therapy for a specific patient. The former erodes shared decision-making; the latter embodies it.

Beyond Myasthenia Gravis

Although gMG provides a timely example, similar access issues are emerging across neuromuscular medicine. Efgartigimod has undergone HTA for chronic inflammatory demyelinating polyradiculoneuropathy, and other targeted immunotherapies are expanding across autoimmune neuromuscular disorders. In inherited neuromuscular disease, similar tensions already exist around access to high-cost therapies, genetic testing, infusion infrastructure and provincial eligibility criteria.

Without a more coherent approach, the same pattern will repeat: regulatory approval, national review, provincial variability, administrative restriction and inequitable patient access. The problem is structural, not disease-specific.

Toward a More Rational Framework

Cost containment is necessary in publicly funded health care. However, stewardship should be evidence-aligned, clinically coherent and equitable. Provincial criteria for newly approved neuromuscular therapies should be transparent, publicly accessible and comparable across provinces. Where provincial criteria deviate from CDA reimbursement recommendations, the rationale should be explicit, publicly accessible and subject to periodic review with input from disease experts and patient representatives.

Specialist-led exception pathways should be available when fail-first requirements are clinically inappropriate, and these pathways should be timely and predictable. Criteria should be revisited regularly as evidence evolves. Neurologists, patient organizations (such as Muscular Dystrophy Canada) and disease-specific networks, such as the Neuromuscular Disease Network for Canada, should be meaningfully consulted before restrictive criteria are adopted.

A more transparent approach would also benefit provincial drug programs by reducing repeated appeals, improving consistency in adjudication and clarifying expectations for clinicians and patients. Equity and stewardship should not be treated as opposing goals; a coherent reimbursement framework can support both by ensuring that targeted therapies are used for appropriate patients without imposing clinically arbitrary sequencing requirements.

Most importantly, reimbursement frameworks should distinguish between therapies that are reasonable clinical options and therapies that are administratively required before another treatment can be accessed. These are fundamentally different policy choices. One approach preserves individualized, specialist-led decision-making, while the other risks allowing reimbursement criteria to supersede clinical judgment.

Conclusion

The promise of targeted therapy in neuromuscular disease will only be realized if access is transparent, timely and equitable. Canadian neuromuscular patients deserve better than a system in which approval does not mean access, national review does not ensure provincial consistency and evidence-based treatment is delayed by administratively mandated treatment sequences.

As new therapies arrive across neuromuscular medicine, postal code and fail-first logic should not determine who benefits from scientific progress.