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#Infografía
enero 2023

Pathophysiology of NMOSD and the Role of IL-6

enero 2023
​ Neuroscience
​

NMOSD disease mechanisms overview

Refresh your memory on the workings of NMOSD 

NMOSD is a rare, debilitating autoimmune disease of the CNS, characterized by lesions in the spinal cord, optic nerve, and brain stem

NMOSD is a heterogeneous disease with a complex and multifaceted pathophysiology

In NMOSD, symptoms are caused by a combination of:

  • Immune-mediated demyelination1–3
  • Damage to axons in the spinal cord, optic nerve, and brainstem2,3
  • Astrocyte death3
  • Rapid loss of oligodendrocytes and their precursors1,3

The exact mechanisms by which neurologic injury occurs are not fully understood, but a number of inflammatory processes have been found to drive NMOSD disease activity

CNS, central nervous system; NMOSD, neuromyelitis optica spectrum disorder.  

The following three proteins are all associated with NMOSD pathophysiology, and will be covered in this module

AQP4-IgG A

A pathogenic autoantibody against aquaporin-4 (AQP4)

Interleukin-6 (IL-6) 

A pleiotropic (i.e. multifunctional) cytokine 

MOG-IgG A

pathogenic antibody against myelin oligodendrocyte glycoprotein (MOG)

AQP4, aquaporin-4; AQP4-IgG, aquaporin-4 immunoglobulin G; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G.

Summary

NMOSD is a complex, heterogeneous disease, with two thirds of patients expressing pathogenic autoantibodies against AQP4 (AQP4-IgG)

One third of patients with NMOSD are AQP4-IgG seronegative; more research is needed to understand the pathophysiology of disease in these patients

IL-6, a multi-functional cytokine, plays a critical role in the pathogenesis of NMOSD by stimulating proinflammatory immune cells, leading to BBB disruption and CNS damage

Antibodies against MOG (MOG-IgG) have been identified in patients with NMOSD, but the neurology community is currently trending towards classification as separate disease entity, termed MOG-AD

AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood–brain barrier; CNS, central nervous system; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOG-AD, MOG-antibody associated disease; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder.

Referencias

  1. Papadopoulos MC, et al. Nat Rev Neurol 2014;10:493–506.
  2. Wingerchuk DM, et al. Lancet Neurol 2007;6:805–815.
  3. Wrzos C, et al. Acta Neuropathol 2014;127:523–538.
  4. NHS NMO UK. Neuromelitis Optica – A Guide to the Condition. 2012. Available at: http://www.nmouk.nhs.uk/wp-content/uploads/2016/12/NMO-A-Guide_Lo-Res-2.pdf. Accessed November 2020.

The Role of AQP4-IgG in NMOSD

Understand AQP4 and the role of autoantibodies against AQP4 in the pathogenesis of NMOSD

Aquaporin-4 (AQP4), a water channel protein expressed primarily in the CNS, has an important role in regulating the brain water balance

AQP4 is the most abundant water channel in the CNS1 and is involved in brain and spinal cord water balance and neuroexcitatory processes2 

AQP4 is involved in regulating water balance in the brain, facilitating high water permeability across the blood–brain and blood–CSF barriers2 

AQP4 is expressed in astrocytes throughout the CNS, and is primarily localized on the astrocytic end-feet surrounding the blood vessels or subarachnoid space3

AQP4, aquaporin-4; BBB, blood–brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid. 

Pathological autoantibodies against AQP4 (AQP4-IgG) are found in at least two-thirds of patients with NMOSD 

Serum autoantibodies against AQP4, called AQP4-IgG, are present in at least two-thirds of patients with NMOSD4

  • Individuals are often categorized based on whether their NMOSD is AQP4-IgG seropositive or AQP4-IgG seronegative

AQP4-IgG antibodies are directly pathogenic and play an important role in mediating the pathophysiology in NMOSD5,6

Importantly, AQP4-IgG antibodies are not found in healthy persons or those with other neurological conditions such as MS7–9

AQP4-IgG

AQP4, aquaporin 4; AQP4-IgG, aquaporin-4 immunoglobulin G; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder.  

The current hypothesis for AQP4-IgG-seropositive NMOSD pathogenesis involves the binding of AQP4-IgG to AQP4 on astrocyte end-feet10

AQP4, aquaporin 4; AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

AQP4-IgG-seropositive patients appear to respond better to NMOSD treatment than seronegative patients11–13

Because of the differences in NMOSD pathophysiology, AQP4-IgG seropositivity can affect disease and treatment outcomes

AQP4-IgG-seropositive patients tend to experience a more severe disease course than their seronegative counterparts14–16

Clinical trials into the latest NMOSD therapies suggest that AQP4-IgG seropositive patients may respond better to treatment than seronegative patients11–13

  • Currently, dedicated NMOSD therapies are only approved for use in AQP4-IgG seropositive NMOSD17–19

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Summary

NMOSD is a complex, heterogeneous disease, with two thirds of patients expressing pathogenic autoantibodies against AQP4 (AQP4-IgG)

One third of patients with NMOSD are AQP4-IgG seronegative; more research is needed to understand the pathophysiology of disease in these patients

IL-6, a multi-functional cytokine, plays a critical role in the pathogenesis of NMOSD by stimulating proinflammatory immune cells, leading to BBB disruption and CNS damage

Antibodies against MOG (MOG-IgG) have been identified in patients with NMOSD, but the neurology community is currently trending towards classification as separate disease entity, termed MOG-AD

AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood–brain barrier; CNS, central nervous system; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOG-AD, MOG-antibody associated disease; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder.

Referencias

  1. Jarius S, et al. Brain Pathol 2013;23:661–683.
  2. Verkman AS. Annu Rev Med 2012;63:303–316.
  3. Nagelhus EA, et al. Neuroscience 2004;129:905–913.
  4. Wingerchuk DM, et al. Neurology 2015;85:177–189;
  5. Roemer SF, et al. Brain 2007;130:1194–1205.
  6. Saadoun S, et al. Brain 2010;133:349–361.
  7. Jarius S, Wildemann B. Brain Pathol 2013;23:661–683.
  8. Lennon VA, et al. Lancet 2004;364:2106– 2112.
  9. Chihara N, et al. Proc Natl Acad Sci USA 2011;108:3701–3706.
  10. Papadopoulos MC, et al. Nat Rev Neurol 2014;10:493-506.
  11. Sherman E, Han MH. Curr Treat Options Neurol 2015;17:48.
  12. Jarius S, et al. J Neuroinflammation 2012;9:14.
  13. Tanaka M, et al. Eur Neurol 2009;62:167–170.
  14. Cree BAC, et al. Lancet 2019;394:1352–1363.
  15. Traboulsee A, et al. Lancet Neurol 2020;19:402–412.
  16. Yamamura T, et al. N Engl J Med 2019;381:2114–2124.
  17. US Food and Drug Administration. Available at: Link. Published June 27, 2019. Accessed September 2020.
  18. US Food and Drug Administration. Available at: Link. Published August 17, 2020. Accessed September 2020.
  19. US Food and Drug Administration. Available at: Link. Published June 11, 2020. Accessed September 2020.

The Role of IL-6 in NMOSD

Understand IL-6 and the role of IL-6 in the pathogenesis of NMOSD

IL-6 is a soluble, multifunctional cytokine that plays a key role in a variety of cellular biological processes1–3

CRP, C-reactive protein; IL-6, interleukin-6; RANKL, receptor activator of nuclear factor kappa-Β ligand; Th17, T-helper cell 17; Treg, regulatory T cell; VEGF, vascular endothelial growth factor. 

IL-6 receptor signaling plays a key role in mediating the acute-phase response 

APPs are proteins that have plasma concentrations that increase or decrease rapidly in response to inflammation caused by injury or infection

APPs act as inhibitors or mediators of inflammatory processes, and include CRP and SAA

The production of APPs is stimulated by pro-inflammatory cytokines, such as TNF-ꭤ, IL-1, and IL-6

Changes in plasma APP concentrations are used as a clinical guide to diagnosis and management, as they reflect both the presence and intensity of inflammation 

APP, acute-phase protein; CRP, C-reactive protein; IL-1/6, interleukin-1/6; SAA, serum amyloid A; TNF-α, tumor necrosis factor-α. Gabay C, Kushner I. N Engl J Med 1999;340:448–454.

IL-6 induces downstream intracellular IL-6R signaling mainly through the JAK-STAT pathway4,5

Classic signaling

  • In classic signaling, IL-6 binds to the membrane-bound IL-6R (mIL-6R)
  • Classic signaling can only take place in cells that contain mIL-6R (hepatocytes, some epithelial cells and certain types of leukocytes)4,5
  • As mIL-6R is not expressed in the central nervous system, classic signaling is unlikely to play a role in NMOSD pathophysiology

Trans-signaling

  • In trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), before forming a membrane complex with gp130 (a transmembrane glycoprotein essential for IL-6R downstream signaling)
  • All cells express gp130, so trans-signaling is possible throughout the body, including the central nervous system
  • It is likely that the IL-6 signaling associated with NMOSD is trans-signaling6 

gp, glycoprotein; IL-6, interleukin-6; IL-6R, IL-6 receptor; JAK-STAT, Janus kinase/signal transducer and activator of transcription; mIL-6R, membrane-bound IL-6 receptor; NMOSD, neuromyelitis optica spectrum disorder; sIL-6R, soluble IL-6 receptor. 

Persistent, dysregulated production of IL-6 plays a critical role in the pathogenesis of several chronic autoimmune diseases3,7–11

IL-6, interleukin-6; NMOSD, neuromyelitis optica spectrum disorder. 

In NMOSD, IL-6 promotes the formation of inflammatory Th17 cells, and stimulates the secretion of pathogenic AQP4-IgG 

1. Activation of the autoimmune cascade 

1  IL-6 induces T cell polarization, shifting the Treg-Th17 balance towards an inflammatory Th17 phenotype12

2  IL-6 stimulates the differentiation of B cells into plasmablasts, which are the main cells responsible for producing pathogenic AQP4-IgG13–15

3  IL-6 promotes the survival of plasmablasts, as well as increasing how much AQP4-IgG they secrete13–15

AQP4, aquaporin-4; AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood-brain barrier; CDC, complement dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; MAC; membrane attack complex; Treg, regulatory T cell. 

IL-6 disrupts the blood–brain barrier, allowing autoantibodies and pro-inflammatory immune cells into the central nervous system

2. Disruption of the blood–brain barrier 

1  IL-6 increases BBB permeability, enabling the infiltration of 1 AQP4-IgG and other autoantibodies into the CNS16,17

2  By increasing BBB permeability, IL-6 also allows pro-inflammatory cells such as neutrophils, monocytes and eosinophils into the CNS16–18

AQP4, aquaporin-4; AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood-brain barrier; CDC, complement dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; CNS, central nervous system; IL-6, interleukin-6; MAC; membrane attack complex; Treg, regulatory T cell 

IL-6 contributes indirectly to astrocyte injury, secondary demyelination and neuronal damage

3. Indirect astrocyte injury

1  After entering the CNS, AQP4-IgG binds to AQP4 water channels on the end-feet of astrocytes – this activates the complement cascade, which results in astrocyte injury19,17

2  Granulocytes, which have entered the CNS through the BBB, release pro-inflammatory cytokines (e.g. IL-1β, TNF-α) that cause astrocytes to secrete more IL-6, creating a positive feedback loop19

3  IIncreased IL-6 levels promote secondary demyelination and contribute to oligodendrocyte and axonal damage, leading to neuronal death19,17,20

AQP4, aquaporin-4; AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood–brain barrier; CNS, central nervous system; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α. 

CSF and serum IL-6 concentrations are significantly elevated in patients with active NMOSD, but not in patients with MS 

AQP4+, aquaporin-4 immunoglobulin G positive; CSF, cerebrospinal fluid; IL-6, interleukin-6; MS, multiple sclerosis; MOG+, myelin oligodendrocyte glycoprotein immunoglobulin G positive; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; OND(s), (other) non-inflammatory neurological disorders/diseases; PPMS, primary progressive multiple sclerosis; RRMS, relapsing remitting multiple sclerosis

IL-6 levels appear to correlate with baseline clinical severity and relapse risk in NMOSD, and are elevated in the serum and CSF during relapse22,24,21

CSF, cerebrospinal fluid; EDSS, Expanded Disability Status Scale; IL-6, interleukin-6; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder. 

Summary

NMOSD is a complex, heterogeneous disease, with two thirds of patients expressing pathogenic autoantibodies against AQP4 (AQP4-IgG)

One third of patients with NMOSD are AQP4-IgG seronegative; more research is needed to understand the pathophysiology of disease in these patients

IL-6, a multi-functional cytokine, plays a critical role in the pathogenesis of NMOSD by stimulating proinflammatory immune cells, leading to BBB disruption and CNS damage

Antibodies against MOG (MOG-IgG) have been identified in patients with NMOSD, but the neurology community is currently trending towards classification as separate disease entity, termed MOG-AD

AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood–brain barrier; CNS, central nervous system; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOG-AD, MOG-antibody associated disease; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder.

Referencias

  1. Tanaka T, Kishimoto T. Int J Biol Sci 2012;8:1227–1236.
  2. Tanaka T, et al. Cold Spring Harb Perspect Biol 2014;6:a016295.
  3. Kamimura D, et al. Rev Physiol Biochem Pharmacol 2003;149:1–38.
  4. Hunter CA, Jones SA. Nat Immunol 2015;16:448–457
  5. Rose-John S. Int J Biol Sci 2012;8:1237–1247.
  6. Araki M, et al. Neurology 2014;82:1302–1306.
  7. Gottschalk TA, et al. Front Immunol 2015;6:550.
  8. Maggio M, et al. J Gerontol A Biol Sci Med Sci 2006;61:575–584.
  9. Içöz S, et al. Int J Neurosci 2010;120:71–75.
  10. Uzawa A, et al. Clin Exp NeuroImmunol 2013;4:167–172.
  11. Gabay C. Arthritis Res Ther 2006;8(suppl 2):S3
  12. Kimura A, Kishimoto T. Eur J Immunol 2010;40:1830–5.
  13. Kawano MM, et al. Blood 1995;85:487–94
  14. Yoshizaki K, et al. J Immunol 1984;132:2948–54.
  15. Chihara N, et al. Proc Natl Acad Sci USA 2011;108:3701–6.
  16. Takeshita Y, et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e311.
  17. Traboulsee A, et al. Lancet Neurology 2020;19:402-412.
  18. Obermeier B, et al. Nat Med 2013;19:1584–1596.
  19. Erta M, et al. Int J Biol Sci 2012;8:1254–1266.
  20. Papadopoulos MC, et al. Nat Rev Neurol 2014;10:493–506.
  21. Uzawa A, et al. Mult Scler 2010;16:1443–1452.
  22. Matsushita T, et al. PLoS One 2013;8:e61835.
  23. Kaneko K, et al. J Neurol Neurosurg Psychiatry 2018;89:927–936.
  24. Barros PO, et al. Clin Exp Immunol 2016;183:480–489.

AQP4-IgG-seronegative NMOSD, and the role of MOG-IgG 

Gain an overview of AQP4-IgG-seronegative NMOSD, including the role of MOG-IgG

Up to one third of patients are AQP4-IgG seronegative, and NMOSD pathophysiology is poorly understood in this population

The existence of seronegative patients with NMOSD indicates that AQP4-IgG-independent disease mechanisms are involved1

  • Disease pathophysiology is poorly understood in this population, so treating seronegative patients is difficult
  • Diagnosis of NMOSD also becomes more challenging in the absence AQP4-IgG - criteria require patients to display at least two core clinical characteristics, instead of one core characteristic plus AQP4-IgG serology2

Up to 42% of AQP4-IgG-seronegative patients express myelin oligodendrocyte glycoprotein (MOG) antibodies1 , though it is unclear whether these are causative agents or are secondary to tissue damage3

Compared to AQP4-IgG-seropositive patients, individuals with NMOSD who are MOG-IgG seropositive show a more variable disease course, and are:4,5

  • Equally likely to be male or female (AQP4-IgG is more common in females)
  • Usually younger at the time of disease onset
  • More likely to display isolated optic neuritis or myelitis
  • More likely to have brain involvement 

AQP4, aquaporin 4; AQP4-IgG, aquaporin-4 immunoglobulin G; MOG, myelin oligodendrocyte glycoprotein; NMOSD, neuromyelitis optica spectrum disorder. 

The role of MOG-IgG in NMOSD pathogenesis remains unclear 

  • If a patient tests positive for MOG-IgG, that does not necessarily mean that they have NMOSD
  • Although a significant proportion of MOG-IgG-seropositive individuals experience the hallmark symptoms of NMOSD,6-8 many do not fulfil NMOSD criteria
    • In a study of 170 MOG-IgG-seropositive patients, only 25% met the criteria for AQP4-IgG-seronegative NMOSD9
  • Rather than being seen as a subcategory of NMOSD, the latest evidence suggests that MOG-antibody associated disease (MOG-AD) is a separate condition that overlaps with AQP4-IgG-seronegative NMOSD10-12 (Figure)

AQP4-IgG, aquaporin-4 immunoglobulin G; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

MOG-IgG-positive NMOSD patients have significantly fewer subsequent relapses and better outcomes than AQP4-IgG-positive patients

Differences were significant – *P<0.00014 ; ^P=0.025 ;**P=0.05; †P=0.03; ‡P=0.0031; #Assessed by EDSS and visual acuity. AQP4-IgG, aquaporin-4 immunoglobulin G; EDSS, Expanded Disability Status Scale; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; MRI, magnetic resonance imaging; NMOSD, neuromyelitis optica spectrum disorder; ON, optic neuritis; SD, standard deviation

Cell-based assays are the preferred choice for AQP4-IgG and MOG-IgG serological testing

AQP4-IgG testing
 

  • Recommended in patients with the following17 :
    • Recurrent, bilateral or severe optic neuritis
    • Longitudinal, or recurrent transverse myelitis
    • Lumbar MRI spine shows a lesion over >3 vertebrae
    • Poor recovery from MS relapses
       
  • In AQP4-IgG testing, cell-based assays are specific and more sensitive than tissue-based immunofluorescence or ELISA3,18

  • Assays detecting IgG binding to cells expressing recombinant AQP4 with quantitative flow cytometry detect 77% of AQP4-IgG-seropositive patients18

MOG-IgG testing 
 

  • Recommended in patients with the following11 :
    • Monophasic or relapsing acute optic neuritis, myelitis, or encephalitis
    • Radiological findings compatible with CNS demyelination
    • MRI/CSF/Histopathology suggestive of acute CNS demyelination of putative autoimmune etiology
       
  • MOG-IgG testing should not be restricted to AQP4-IgG-seronegative patients11

  • A cell-based assay, using full-length human MOG as a target antigen and IgG1-specific antibodies, should be used11

  • MOG-IgG serum concentrations depend on disease activity, so patients should be re-tested during an acute attack if the initial assay was negative11

AQP4, aquaporin 4; AQP4-IgG, aquaporin-4 immunoglobulin G; CNS, central nervous system; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; MOG, myelin oligodendrocyte glycoprotein; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; MRI, magnetic resonance imaging; MS, multiple sclerosis.

Therapeutic agents for the treatment of NMOSD are designed to affect a number of different targets involved in the disease pathophysiology 

APRIL, A proliferation-inducing ligand (also known as TNFSF13, tumor necrosis factor ligand superfamily member 13); AQP4-IgG, aquaporin-4 IgG immunoglobulin G; BBB, blood–brain barrier; BLyS, B-lymphocyte stimulator; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; mAb, monoclonal antibody; NMOSD, neuromyelitis optica spectrum disorder. 

Summary

NMOSD is a complex, heterogeneous disease, with two thirds of patients expressing pathogenic autoantibodies against AQP4 (AQP4-IgG)

One third of patients with NMOSD are AQP4-IgG seronegative; more research is needed to understand the pathophysiology of disease in these patients

IL-6, a multi-functional cytokine, plays a critical role in the pathogenesis of NMOSD by stimulating proinflammatory immune cells, leading to BBB disruption and CNS damage

Antibodies against MOG (MOG-IgG) have been identified in patients with NMOSD, but the neurology community is currently trending towards classification as separate disease entity, termed MOG-AD

AQP4-IgG, aquaporin-4 immunoglobulin G; BBB, blood–brain barrier; CNS, central nervous system; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOG-AD, MOG-antibody associated disease; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder.

Referencias

  1. Narayan R, et al. Mult Scler Relat Disord 2018;25:66–72.
  2. Wingerchuk DM, et al. Neurology 2015;85:177–89.
  3. Fujihara K. Curr Op Neurol 2019;32:385–94.
  4. de Seze J. Brain 2017;140:3069–80.
  5. de Seze J. Curr Opin Neurol 2019;32:111–4.
  6. Jarius S, et al. J Neuroinflammation 2016;13:279.
  7. Ramanathan S, et al. Neurol Neuroimmunol Neuroinflamm 2014;1:e40.
  8. Kezuka T, et al. J Neuroophthalmol 2012;32:107–10.
  9. Kunchok A, et al. JAMA Neurol 2020:e202743.
  10. de Seze J. Curr Opin Neurol 2019;32:111–14 6
  11. Jarius S, et al. J Neuroinflammation 2018;15:134.
  12. Dos Passos GR, et al. Front Neurol. 2018;9:217.
  13. Jarius S, et al. J Neuroinflammation 2016;13:280.
  14. Kezuka T, et al. J Neuroophthalmol 2012;32:107-110.
  15. Sato DK, et al. Neurology 2014;82:474-481.
  16. Kitley J, et al. JAMA Neurol 2014;71:276–283.
  17. Aquaporin 4 –antibodies (AQP4). Available at: Link (Accessed September 2020).
  18. Waters PJ, et al. Neurology 2012;78:665–71.
  19. Roche. Press Release. Available at: Link. June 29, 2020. Accessed August 2020.
  20. Uplizna™ (Inebilizumab) prescribing information. June 2020.
  21. Biospace Remegen. Press Release. Available at: Link. Accessed April 2020.
  22. Alexion Pharmaceuticals. Available at: Link. Published June 27, 2019. Accessed June 2020.
  23. Soliris® (eculizumab) Prescribing Information. June 2019.
  24. Alexion.com. Ravulizumab data release. Available at: Link. Accessed April 2020.
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