The therapeutic armamentarium at the center of the article acts at different levels of the pathogenic cascade. The neonatal Fc receptor antagonists efgartigimod alfa and rozanolixizumab promote the degradation of circulating pathogenic IgG antibodies, giving them a rapid onset of action and a favorable safety profile. Ravulizumab, a long-acting terminal C5 complement inhibitor, acts downstream by preventing formation of the membrane attack complex and complement-mediated injury at the postsynaptic membrane; the CHAMPION MG trial confirmed rapid and lasting improvement in acetylcholine receptor antibody-positive generalized myasthenia gravis with maintenance dosing every eight weeks. Rituximab, by contrast, acts upstream by depleting CD20-positive B cells and may provide long-term immunosuppressive effect; in the RINOMAX randomized trial, rituximab given within twelve months of diagnosis increased the probability of achieving minimal disease manifestations and reduced the need for rescue treatment compared with placebo.

The Athens team retrospectively described seven purposively selected adults managed between February 2025 and July 2026, distinguishing therapies that had actually been administered from those merely planned at the data cutoff. Treatment selection was guided by disease severity, corticosteroid-related risks, presence of thymoma, comorbidities, peripheral venous access, vaccination requirements and the need for rapid improvement or sustained disease management. During the study period, efgartigimod alfa and rozanolixizumab were the only FcRn antagonists and ravulizumab the only C5 complement inhibitor commercially available in Greece, a practical constraint that shaped the pathways. Follow-up under the targeted strategy ranged from one to twelve months, and no treatment-related side effects, relevant infections or rescue therapies for worsening disease were recorded.

Three of the cases involved recent-onset disease, defined as diagnosis within the preceding twelve months. A 72-year-old man with a four-month history and advanced chronic glaucoma, for which corticosteroid escalation was contraindicated, received four cycles of efgartigimod alfa as a rapidly acting bridging therapy; prednisolone was halved from 15 to 7.5 milligrams per day while clinical stability was maintained, and rituximab was planned as the longer-term non-steroidal strategy. A 71-year-old man with recently diagnosed early-stage prostate cancer and hypertension received two cycles of rozanolixizumab, whose subcutaneous route was clinically practical, with prednisolone reduced from 15 to 12.5 milligrams per day while he completed the vaccinations required before planned rituximab. A 59-year-old man with type 2 diabetes and cardiovascular comorbidities worsened by steroids received a single efgartigimod cycle and reached a Myasthenia Gravis Activities of Daily Living score of 0, with prednisolone reduced from 20 to 17.5 milligrams per day.

A fourth profile involved very-late-onset disease, defined as onset at age 65 or older. An 80-year-old man with two months of predominantly bulbar dysfunction requiring a nasogastric tube received prednisolone, intravenous immunoglobulin and two rituximab infusions of 500 milligrams each, achieving enough improvement to remove the tube. Because dysarthria and dysphagia persisted and his peripheral venous access was poor, rozanolixizumab was initiated nine weeks after the second rituximab infusion as continuing, symptom-guided FcRn inhibition with the practical advantage of subcutaneous administration. After four cycles with intercycle intervals of three to six weeks determined by clinical need, his status improved from class IIIB to IIB, prednisolone fell from 10 to 7.5 milligrams per day, and immunophenotyping six months after rituximab showed CD19-positive cells at 0.5 percent, confirming sustained B-cell depletion.

Two thymoma-associated cases illustrate the bridging logic most vividly. A 46-year-old woman referred eighteen months after diagnosis with severe ocular-cervical-bulbar weakness received prednisolone, intravenous immunoglobulin, plasma exchange and four weekly rituximab infusions, yet disabling neck flexor weakness, nasal speech and dysarthria persisted. Efgartigimod was started eleven months after the rituximab course; after three cycles at seven-week intervals, prednisolone was reduced from 20 to 10 milligrams per day, and ravulizumab was intended as long-term therapy once required vaccinations were completed. A 48-year-old woman whose thymoma was removed incidentally, and who also carried a history of HPV-associated cervical adenocarcinoma, had poor venous access that precluded further plasma exchange; two efgartigimod cycles improved her from class IVB to IIA with an MG-ADL score of 1, while meningococcal vaccination proceeded toward planned ravulizumab. The choice is supported by growing real-world evidence, including an Italian multicenter ravulizumab cohort of 14 thymoma patients showing greater early Quantitative Myasthenia Gravis response in this subgroup, and a separate cohort of 23 patients confirming complement inhibitor effectiveness in thymoma-associated disease.

The seventh case involved chronic, corticosteroid-dependent disease with prominent ocular relapse. A 71-year-old man with a seven-year history had achieved pharmacological remission on mycophenolate mofetil and low-dose alternate-day prednisolone, then developed an unprovoked ocular-bulbar relapse with severe bilateral ptosis and diplopia. Prednisolone was raised to 25 milligrams per day, and symptom recurrence during tapering indicated inadequate control despite mycophenolate. Three efgartigimod cycles improved his MG-ADL score from 7 to 2 and his class from IIIB to IIB, but residual ptosis tended to recur as each cycle approached, precluding steroid reduction. Ravulizumab was therefore planned for sustained control, a rationale reinforced by a post hoc analysis of CHAMPION MG showing benefit across individual MG-ADL items, with particularly notable improvements in ocular symptoms including eyelid ptosis and diplopia.

The article also highlights practical pharmacology that determines sequencing. Clinically meaningful improvement with efgartigimod may appear as early as one week after the first administration, with maximal benefit generally around week four, while rozanolixizumab improvement has been detected from day eight, the first post-baseline assessment. FcRn antagonists require no pre-treatment vaccinations, allowing immediate initiation, whereas C5 complement inhibition demands meningococcal vaccination against serogroups A, C, W, Y and B completed at least two weeks before the first ravulizumab dose, with antibacterial prophylaxis required if treatment must begin sooner. This vaccination delay is precisely why FcRn antagonists served as immediately available bridging therapies in the thymoma and relapsing cases. For planned rituximab transitions, the team uses an interval of at least two to three weeks after the last FcRn dose, reflecting efgartigimod pharmacokinetics and serum IgG recovery preferably above 5 grams per liter, while stressing that no evidence-based interval has been established.

A subtle pharmacokinetic consideration runs through the discussion: because FcRn inhibition enhances IgG catabolism and ravulizumab is an IgG-based monoclonal antibody, FcRn blockade increases ravulizumab clearance, which is why the pathways were sequential rather than concomitant. Japanese clinicians have recently reported two refractory patients treated with combined subcutaneous efgartigimod and zilucoplan, a macrocyclic peptide C5 inhibitor that, not being an IgG antibody, escapes FcRn-mediated catabolism; zilucoplan was not commercially available in Greece during the study period. The authors are candid about limitations, including the retrospective single-center design, very small and heterogeneous sample, potential selection bias and the fact that several planned transitions had not yet been implemented, making the observations descriptive and hypothesis-generating rather than proof of comparative efficacy. Still, the seven pathways assign distinct but complementary clinical roles to each agent, rapid IgG reduction, long-term B-cell depletion and sustained terminal complement inhibition, and argue that treatment sequence should be tailored to disease phenotype, therapeutic objective, comorbidities, vaccination requirements and route of administration, with prospective studies needed to establish optimal intervals and biomarkers capable of guiding individualized selection.

Subject of Research: Neurology

Article Title: Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles

Article References: Zouvelou, V., Tzavella, D., Strataki, E., & Vakrakou, A. G. (2026). Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles. Frontiers in Neurology, 17, Article 1989043. https://doi.org/10.3389/fneur.2026.1989043

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DOI: 10.3389/fneur.2026.1989043

Keywords: myasthenia gravis, immunotherapy, FcRn antagonists, rituximab, ravulizumab, neuromuscular disorders, targeted therapy, Individualized, sequencing, targeted, immunotherapies, generalized

To understand why this analysis matters, it helps to grasp what these drugs actually do. Ravulizumab is a monoclonal antibody that blocks the terminal pathway of the complement system, a branch of innate immunity that normally helps destroy pathogens and damaged cells. In pregnancy, complement activity is tightly choreographed to protect the developing placenta while maintaining immunological tolerance between mother and fetus. But in a group of rare, complement-mediated disorders, this system turns against the body’s own tissues. In paroxysmal nocturnal hemoglobinuria, or PNH, uncontrolled complement activation destroys red blood cells and drives life-threatening blood clots. In atypical hemolytic uremic syndrome, or aHUS, it attacks the small vessels of the kidneys. In generalized myasthenia gravis and neuromyelitis optica spectrum disorder, antibody-driven complement activation damages the neuromuscular junction and the optic nerves and spinal cord, respectively. When pregnancy superimposes its own physiological upheaval on these already volatile conditions, the result can be disease flares, hemolysis, thrombosis, kidney failure, and serious fetal complications.

The historical numbers explain why pregnancy was once actively discouraged in these patients. Before complement blockers arrived, maternal mortality in pregnant women with PNH ranged from 8 to 21 percent, driven largely by postpartum thrombosis, with fetal mortality estimated at 4 to 9 percent. In aHUS, maternal mortality was reported at around 5 percent, and women faced high risks of progressing to chronic kidney disease, end-stage kidney disease, and dialysis dependence, alongside fetal dangers including intrauterine death, growth restriction, low birth weight, and prematurity. In myasthenia gravis, at least one-third of patients experience symptom worsening during pregnancy, particularly in the first trimester and after delivery. And in NMOSD, pregnancy is associated with increased relapse risk and elevated rates of miscarriage, reported at 22.6 percent, along with premature delivery and preeclampsia. Against this backdrop, the arrival of eculizumab, the first terminal complement C5 inhibitor approved in the United States in 2007, transformed the calculus, allowing many women with these disorders to carry pregnancies safely for the first time.

Ravulizumab, approved by the FDA in 2018, was engineered from eculizumab with an improved pharmacokinetic profile that allows immediate, complete, and sustained terminal complement inhibition with much longer intervals between doses. That pharmacological advantage, however, came with an evidentiary disadvantage: because the drug had been on the market for a shorter time, its pregnancy safety data were limited largely to scattered case reports and small case series. The new analysis, conducted by researchers at Alexion, AstraZeneca Rare Disease, set out to close that gap by mining the company’s global pharmacovigilance database, which collects adverse event reports from solicited sources such as patient support programs and disease registries, spontaneous reports from healthcare professionals, patients, and regulators, and structured literature searches. Every pregnancy case in which the mother received at least one dose of ravulizumab was captured, regardless of how complete the report was, and duplicate reports of the same pregnancy were consolidated to avoid double counting.

The dataset spans 25 countries across Australia, the Americas, Europe, the Middle East, and Asia-Pacific, covering the period from December 21, 2018, when ravulizumab was first authorized, through December 31, 2025. Of the 354 reported pregnancy cases, the largest group involved women with PNH, at 160 cases, followed by aHUS with 72, generalized myasthenia gravis with 38, and NMOSD with 34; in 45 cases the underlying indication was not reported, and five involved other conditions. Pregnancy outcomes were available for only 106 of these cases, or 29.9 percent, with the remainder unavailable because of ongoing pregnancies, reporting lag, or data and privacy limitations. Among those 106 cases with known outcomes, there were 68 live births, or 64.2 percent, 29 spontaneous abortions, or 27.4 percent, three fetal deaths, or 2.8 percent, and six elective terminations, or 5.7 percent. Most of the outcome-documented cases came from the United States, followed by Japan, Germany, and the United Kingdom.

Exposure patterns varied considerably. Among cases with outcome data, only 17 percent involved ravulizumab exposure throughout the entire pregnancy, while 24.5 percent involved a switch from ravulizumab to eculizumab at some point during gestation, and in 58.5 percent of cases the exposure details were incomplete. To sharpen the picture, the researchers examined a nested subset of 44 post-marketing cases with detailed exposure information and known outcomes. In this subset, live births accounted for 72.7 percent of pregnancies, spontaneous abortions for 25 percent, and one elective termination. The live births included 17 pregnancies in which the mother received ravulizumab through all three trimesters, three in which exposure continued beyond 12 weeks but stopped before delivery, and 11 with first-trimester-only exposure. Because ravulizumab has a long half-life, the authors note, even limited early exposure is clinically relevant, since the drug persists in circulation long after the last infusion.

Perhaps the most striking finding is what did not appear. Among the detailed subset of 44 cases, no maternal deaths were reported, and there were no events suggesting inadequate disease control, such as major thrombotic events, in women receiving ravulizumab during pregnancy. Reported complications, which included thrombocytopenia, renal failure, pre-eclampsia, anemia, breakthrough hemolysis, one myasthenic crisis in a patient with myasthenia gravis, and assorted comorbidities such as chronic kidney disease and cirrhosis, reflect the serious underlying illnesses of the patient population rather than a clear drug-specific pattern. The live birth rate in the full outcome-documented cohort, 64.2 percent, compares favorably with the roughly 70 percent live birth rate reported in a ten-year pharmacovigilance analysis of eculizumab in pregnant women with PNH or aHUS, and the fetal death rate of 2.8 percent was actually lower than the 3.5 percent observed with eculizumab. The authors acknowledge that the spontaneous abortion figure may look elevated at first glance, but they attribute this largely to the small number of cases with available outcome data and note that the rate is similar to that seen in pregnancies complicated by other chronic illnesses.

The new analysis also dovetails with a growing body of clinical literature. A recent case series of 19 ravulizumab-exposed pregnancies reported favorable maternal and fetal outcomes, with every pregnancy ending in a live birth, and individual case reports have described positive outcomes in women with aHUS and NMOSD as well as PNH. One particularly intriguing report documented transplacental transfer of ravulizumab and neonatal complement inhibition in a pregnancy complicated by NMOSD, yet the infant showed no adverse effects. That observation raises questions that only systematic follow-up can answer, since fetal exposure to a complement-blocking antibody could in principle affect the newborn’s developing immune defenses, even when no immediate harm is evident. It is precisely these kinds of subtle, delayed effects that spontaneous pharmacovigilance reporting is least equipped to detect, which is why the authors and independent experts alike emphasize the need for prospective data.

That need is being addressed. Alexion has launched a global observational ravulizumab pregnancy registry, registered as NCT06312644, spanning Australia, France, Germany, Italy, South Korea, the United Kingdom, and the United States. The study enrolls women exposed to ravulizumab at any point from up to 40 weeks before conception through pregnancy or breastfeeding, and follows infants through the first 52 weeks of life, aiming to systematically capture maternal, fetal, and neonatal outcomes. Until those data mature, the current analysis offers a cautiously reassuring signal rather than a definitive verdict. The authors are candid about the limitations inherent to post-marketing surveillance: there are no patient-level identifiers, no comparator groups, no way to calculate true incidence rates, and no capacity for longitudinal follow-up, and reporting bias toward unfavorable outcomes may inflate apparent risks. Still, within those constraints, the message is consistent. Ravulizumab exposure during pregnancy, across more than 48,000 patient-years of global experience, has not produced any safety concerns beyond those already known for its predecessor, and the findings may help clinicians and patients navigate shared decisions about treatment during one of the most medically fraught journeys in modern medicine.

Subject of Research: Real-world pharmacovigilance assessment of ravulizumab safety during pregnancy in complement-mediated disorders

Article Title: Safety of Ravulizumab Use in Pregnancy: Insights from a Global Pharmacovigilance Analysis

Article References: Carrillo Infante, C., Mujeebuddin, A., Koneru, M., & Williams, C. (2026). Safety of Ravulizumab Use in Pregnancy: Insights from a Global Pharmacovigilance Analysis. Advances in Therapy. https://doi.org/10.1007/s12325-026-03816-9

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DOI: 10.1007/s12325-026-03816-9

Keywords: ravulizumab, pregnancy, pharmacovigilance, complement C5 inhibitor, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder, eculizumab, drug safety, real-world evidence, pregnancy outcomes

At its core, the complement cascade is a proteolytic amplification machine. It can be triggered through three converging routes: the classical pathway, initiated when the C1 complex binds antibody-antigen complexes or other target structures; the lectin pathway, ignited when pattern-recognition molecules such as mannose-binding lectin and ficolins detect carbohydrate motifs on pathogens or damaged cells; and the alternative pathway, which samples surfaces continuously through spontaneous hydrolysis and is stabilized by properdin. All three routes converge on C3, whose cleavage generates the opsonin C3b that tags targets for phagocytosis and the anaphylatoxin C3a that recruits and activates inflammatory cells. Further cleavage of C5 releases the potent anaphylatoxin C5a and assembles the C5b-9 membrane attack complex, a pore-forming structure that can lyse susceptible cells. In host defence, this is a marvel of efficiency. In the nervous system, where many cell types are exquisitely vulnerable to lysis and inflammation, the same machinery can become an instrument of destruction.

What makes complement particularly fascinating in a neurological context is that it is not merely a circulating defence system but an active participant in normal brain physiology. Seminal experimental work has shown that classical pathway components, including C1q and C3, physically tag synapses during postnatal development, allowing microglia to prune weak or inactive connections in an activity-dependent manner. This complement-dependent synaptic sculpting is essential for wiring the developing brain, and related mechanisms continue to influence adult neural circuit plasticity, including microglia-mediated elimination of synapses linked to forgetting. The complement system also contributes to the clearance of apoptotic cells and cellular debris, processes fundamental to maintaining tissue health. These physiological roles carry a sobering implication: any therapeutic strategy that blanketly suppresses complement risks interfering with brain development, synaptic maintenance, and debris clearance, a concern that hangs over much of the current drug pipeline.

In autoimmune neurological disease, aberrant complement activation is now documented with striking consistency. In myasthenia gravis, autoantibodies against the acetylcholine receptor recruit complement to the neuromuscular junction, where the membrane attack complex destroys the postsynaptic membrane, a mechanism established experimentally decades ago and confirmed ultrastructurally by localization of the lytic component C9 at the motor end-plate. Complement activation profiles correlate with disease severity, and eculizumab, a monoclonal antibody that blocks cleavage of C5, demonstrated efficacy in refractory generalized disease in the pivotal REGAIN trial, earning regulatory approval and opening the floodgates for a broader class of anti-C5 agents, including the longer-acting ravulizumab and the subcutaneous peptide zilucoplan, alongside newer C5-targeting candidates such as gefurulimab now in phase 3 testing.

The antibody-mediated demyelinating diseases of the central nervous system tell a similarly compelling story. In neuromyelitis optica spectrum disorder, aquaporin-4-specific IgG1 antibodies bind astrocytic endfeet, fix complement, and generate astrogliotic, necrotic lesions; passive transfer experiments show that immunoglobulin G plus complement reproduces the pathology in animals. Blocking C5 with eculizumab dramatically reduced relapse rates in aquaporin-4-positive patients, and ravulizumab has since replicated these results with a more convenient dosing schedule. The related condition, myelin oligodendrocyte glycoprotein antibody-associated disease, displays its own distinctive complement activation signatures, with recent work showing that activation patterns downstream of C5 cleavage differ between MOGAD and aquaporin-4 antibody-positive neuromyelitis optica, and that complement profiles can predict clinical outcomes. In multiple sclerosis, complement deposition is a prominent feature of lesions, oligodendrocytes are peculiarly susceptible to complement lysis even in the absence of antibody, and growing clinical evidence links circulating complement activation products to structural brain damage, disease severity, and disability progression, including in primary progressive disease. Notably, animal studies reveal that some complement components, such as C5-derived signals, may actually facilitate remyelination, reinforcing the argument for nuanced, pathway-selective modulation rather than indiscriminate shutdown.

In disorders of the peripheral nervous system, complement has moved from suspected accomplice to validated therapeutic target. In Guillain-Barré syndrome, autoantibodies against gangliosides on motor nerve terminals and perisynaptic Schwann cells recruit the membrane attack complex, and complement inhibition protects nerve terminals in murine models. Eculizumab was tested in a large phase 3 trial and, although the primary endpoint was not met, encouraging signals and real-world comparative data for the proximal inhibitor ANX005, which blocks C1q, suggest that early, pathway-targeted intervention may still prove valuable. Chronic inflammatory demyelinating polyneuropathy has emerged as a particularly fertile field: recent complement profiling of sural nerves, together with the demonstration that terminal pathway activation tracks with disease severity, has set the stage for phase 2 studies of the C1s inhibitor riliprubart, with promising early efficacy and safety findings. Multifocal motor neuropathy and IgM anti-MAG antibody neuropathies are likewise being reinterpreted through a complement lens, with the C2-blocking antibody empasiprubart, derived from the ARGX-117 program, advancing through clinical development on the logic that IgM-driven complement activation depends critically on the classical pathway component C2.

Perhaps the most provocative frontier is neurodegeneration. In Alzheimer disease, genetic association studies first implicated complement genes as susceptibility loci, and mechanistic work then showed that C1q and C3 drive early synapse loss in mouse models, with microglia engulfing complement-tagged synapses. Complement C3 deficiency protects aged, plaque-laden mice from neurodegeneration, yet other data indicate that specific complement components exert tissue-protective effects, promoting clearance of amyloid debris and supporting repair. Similarly, in amyotrophic lateral sclerosis, elevations of C5a and the membrane attack complex in patient blood and dysregulation of the cascade in the hSOD1G93A mouse model motivated a randomized trial of ravulizumab, which did not slow disease progression but provided dose-finding and safety data that will inform future, more precisely targeted efforts. These mixed results crystallize the central dilemma of the field: complement is both arsonist and firefighter, and the therapeutic challenge is to extinguish the destructive arm of the cascade while preserving its reparative functions.

The authors of the review emphasize that the existing complement drug arsenal, which includes C5 inhibitors such as eculizumab, ravulizumab, and crovalimab; the C1s inhibitor sutimlimab; the C3-targeting peptide pegcetacoplan; factor B and factor D blockers such as iptacopan and danicopan; C1-esterase inhibitor concentrates; and the C2-blocking antibody empasiprubart, was largely forged in hematology, ophthalmology, and nephrology before being imported into neurology. Expanding these agents to the brain raises distinctive pharmacological hurdles, including the blood-brain barrier, the need for sustained pathway suppression in a compartment with limited drug access, and the infection risks inherent in disabling a key arm of host defence, particularly meningococcal disease in patients receiving terminal pathway inhibitors. Proximal inhibitors that block C1 or C2 confer broader cascade suppression and may better preserve certain distal functions, but they carry their own trade-offs in infection susceptibility and disruption of physiological opsonization and debris clearance.

Looking ahead, Dalakas and Lünemann argue that the future of complement-targeted neurology will depend on systematic, biomarker-guided patient selection. Reliable, disease-specific measures of complement activation, whether from cerebrospinal fluid, blood, or tissue, will be essential to identify which patients are most likely to benefit from proximal versus distal inhibition, and to time intervention before irreversible tissue injury has occurred. As biologics targeting other axes of autoimmunity, from FcRn antagonists and neonatal Fc receptor blockers to B-cell-depleting agents and, increasingly, CAR T-cell therapies, crowd the neurological treatment landscape, complement inhibitors will need to demonstrate not just efficacy but a rational, mechanistically defined place in therapeutic algorithms. What is no longer in doubt is the direction of travel: from a system once studied almost exclusively by immunologists, complement has become a frontier of clinical neurology, and the coming decade will determine how precisely medicine can wield its power without extinguishing its gifts.

Subject of Research: The role of the complement system and complement-targeted therapeutics in autoimmune and neurodegenerative neurological diseases

Article Title: Role of complement and complement-targeted therapeutics in neurological diseases

Article References: Dalakas, M. C., & Lünemann, J. D. (2026). Role of complement and complement-targeted therapeutics in neurological diseases. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01261-4

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DOI: 10.1038/s41582-026-01261-4

Keywords: complement system, neuroimmunology, myasthenia gravis, neuromyelitis optica, multiple sclerosis, Guillain-Barré syndrome, Alzheimer disease, amyotrophic lateral sclerosis, eculizumab, ravulizumab, membrane attack complex, complement inhibitors