Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Abstract
  • Introduction
  • Current understanding of complement biology for the clinician
  • Insights into complement potentially applicable to clinical practice
  • Complement in disease
  • Hematology
  • Nephrology
  • Obstetrics: HELLP syndrome
  • Transplantation: transplant-associated thrombotic microangiopathy
  • Rheumatology: antiphospholipid antibody syndrome
  • Neurology
  • Conclusion and future perspectives
  • Acknowledgments
  • Footnotes
  • References
  • Version history
  • Article usage
  • Citations to this article

Advertisement

Review Free access | 10.1172/JCI136094

Complementopathies and precision medicine

Eleni Gavriilaki1 and Robert A. Brodsky2

1Hematology Department, G. Papanicolaou Hospital, Thessaloniki, Greece.

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Robert A. Brodsky, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1025, Baltimore, Maryland 21205, USA. Phone: 410.502.2546; Email: brodsro@jhmi.edu.

Find articles by Gavriilaki, E. in: PubMed | Google Scholar

1Hematology Department, G. Papanicolaou Hospital, Thessaloniki, Greece.

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Robert A. Brodsky, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1025, Baltimore, Maryland 21205, USA. Phone: 410.502.2546; Email: brodsro@jhmi.edu.

Find articles by Brodsky, R. in: PubMed | Google Scholar |

Published April 20, 2020 - More info

Published in Volume 130, Issue 5 on May 1, 2020
J Clin Invest. 2020;130(5):2152–2163. https://doi.org/10.1172/JCI136094.
© 2020 American Society for Clinical Investigation
Published April 20, 2020 - Version history
View PDF
Abstract

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

Introduction

The notion of precision or personalized medicine was introduced in 1999 by Francis Collins based on expected consequences of the Human Genome Project (1). Since then, numerous projects have tried to incorporate genetic and functional disease identities into diagnostic and therapeutic potentials across various disciplines (2). Despite unmet expectations especially in public health issues, precision medicine has expanded, along with a tremendous expansion of complement therapeutics. Indeed, the renaissance of complement therapeutics has led to the recognition of a wide range of complement-mediated disorders, also called “complementopathies” (3). This term has been proposed for disorders in which complement dysregulation drives disease pathogenesis, and complement inhibition has the potential to abate the disease course (4).

Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review comprising (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, neurology, obstetrics, transplantation, and rheumatology), and (d) our perspective on the future development of precision medicine for complementopathies.

Current understanding of complement biology for the clinician

More than 50 soluble and membrane-bound proteins form the complement system, providing innate defense against microbes and mediating inflammatory responses (5, 6). The complement cascade is activated by the classical, alternative, and lectin pathways. Importantly, the alternative pathway of complement serves as an amplification loop for the lectin and classical pathways, accounting for roughly 80% of complement activation products (7).

The classical pathway is mainly activated by antibody-antigen complexes recognized via complement component C1q. Among antibody isotypes, IgM is the most effective in activating complement. Activation of complement with the four subclasses of IgGs varies as a function of steric hindrance by the Fab arms in the approach of C1q to the IgG CH2 sites (IgG3>IgG1>IgG2>IgG4) (8). Besides antibodies, C1q also binds directly to certain epitopes from microorganisms or apoptotic cells and to cell surface molecules, such as acute-phase proteins that bind to pathogens or affected cells and activate complement (9, 10). C1q subsequently cleaves C1r, which activates C1s protease. Then, C1s cleaves C4 and C2, leading to the formation of classical pathway C3 convertase (C4bC2a). C3 convertase cleaves C3, generating the anaphylatoxin C5a and C5 convertase (C4bC2aC3b), which cleaves C5 into C5a and C5b, which initiate the terminal pathway of complement. A schematic of proximal and terminal complement activation is shown in Figure 1.

Targets of complement inhibitors in various stages of clinical developmentFigure 1

Targets of complement inhibitors in various stages of clinical development for complement-mediated disorders. Complement-targeting compounds are shown in red and indicate the step of the complement pathway they target. From left to right: sutimlimab inhibits C1s of the classical pathway; narsoplimab inhibits mannose-binding protein-associated serine protease 2 (MASP-2) of the lectin pathway; pegcetacoplan (formerly APL-2) and AMY-101 inhibit C3 and C3 convertase activity; IONIS-FB-LRx and LPN023 inhibit factor B; lampalizumab and danicopan inhibit factor D; mini-FH/AMY-201 inhibits alternative pathway C3 convertase; CLG561 inhibits properdin; MicroCept inhibits C3 and C5 convertases; eculizumab, ravulizumab, crovalimab, ABP959, tesidolumab, REGN3918, mubodina, coversin, RA101495, cemdisiran, and zimura inhibit C5; and avacopan inhibits C5a receptor; and IFX-1 inhibits C5a.

In the terminal pathway of complement, C5b binds to C6, generating C5b-6, which in turn binds to C7, creating C5b-7. C5b-7 is able to insert into lipid layers of the membrane (11). Once there, C5b-7 binds C8 and C9, forming a complex that unfolds in the membrane and binds several C9 molecules, thereby forming the membrane attack complex (MAC).

Activation of the alternative pathway of complement

The alternative pathway of complement (APC) is summarized by Figure 2. The APC is continuously activated at low levels through slow spontaneous hydrolysis of C3, which forms C3(H2O). This process is called “tickover.” Therefore, the APC can be activated on any surface that has the ability to amplify complement, including the surface of bacteria, apoptotic, and necrotic cells (12). The activated C3(H2O) binds factor B, generating C3(H2O)B. Factor B is subsequently cleaved by factor D, generating the fluid-phase APC C3 convertase, or C3(H2O)Bb. C3 convertase then catalyzes the cleavage of additional C3 molecules to generate C3a and C3b, which attach to cell surfaces (13). This initiates the amplification loop, where C3b pairs with factor B on cell surfaces and bound factor B is cleaved by factor D to generate a second (surface-phase) APC C3 convertase (C3bBb). Membrane-bound C3 convertase then cleaves additional C3 to generate more C3b deposits, closing the amplification loop. The binding and cleavage of an additional C3 molecule to C3 convertase forms the APC C5 convertase (C3bBbC3b) that cleaves C5 to C5a and C5b. C5b initiates the terminal complement pathway that forms the MAC, as described above. The process, from initial spontaneous C3 activation through amplification, is depicted in Figure 1. Both C3 and C5 APC convertases are stabilized by properdin (also known as factor P) (14), which also serves as a selective pattern recognition molecule for de novo C3 APC convertase assembly (12). Properdin is the only known positive regulator of complement. It increases the activity of C3 and C5 convertases, which amplify C3b deposition on cell surfaces (15).

Mutations in complement regulators involved in complement-mediated diseasesFigure 2

Mutations in complement regulators involved in complement-mediated diseases. Complement activation leads to C3 activation and C3 convertase formation on C3-opsonized surfaces, culminating in pronounced C3 fragment deposition on complement-targeted surfaces (proximal complement). In the presence of increased surface density of deposited C3b, the terminal complement is triggered, leading to membrane attack complex (MAC) formation on the surface of target cell. Complement pathway dysregulation results from loss-of-function mutations in regulatory factors (i.e., factor H [FH], factor I [FI], thrombomodulin [THBD], and vitronectin [VTN]) shown in red, gain-of-function mutations (i.e., C3 and factor B [FB]) shown in blue, and DGKE mutations in purple, indicating their unknown effect on complement cascade.

Activation of the lectin pathway of complement

Lectin pathway activation is initiated by mannose-binding lectins (MBLs) that recognize carbohydrate structures on the surfaces of microbes, such as viruses, protozoan parasites, fungi, and various bacteria (16, 17). Other pattern recognition molecules involved in lectin pathway activation are ficolins and collectin 11 (18). These molecules act through MBL-associated serine proteases (MASPs), which generate the C3 convertase (C4bC2a) in a process similar to that of the classical pathway.

Other mechanisms of complement activation have been postulated, including the interaction with the coagulation cascade (discussed below), and heme-induced complement activation (19). Indeed, a plethora of experimental studies have shown that heme interacts with classical and alternative complement pathways (20). This heme-induced complement activation may be relevant in diseases with intravascular hemolysis. Among them, paroxysmal nocturnal hemoglobinuria (PNH) and complement-mediated hemolytic uremic syndrome (CM-HUS) are well-known models of complement activation and will be further discussed below. In others, such as sickle cell disease, the role of complement activation is currently being investigated (21). Excessive complement activation is physiologically prevented by complement-regulatory proteins. Membrane-bound or soluble complement regulators that are relevant to complement-mediated diseases are summarized in Table 1.

Table 1

Complement regulators relevant to complement-mediated disorders

Insights into complement potentially applicable to clinical practice

Immune function of complement

Complement was first recognized to modulate adaptive immunity in the 1970s (22). Since then, a number of studies have investigated molecular pathways of complement interaction with B and T cells (23). Complement modulates innate immune responses by sensing danger signals and interacting with Toll-like receptors (TLRs) (24). Novel pathways have linked complement-mediated signaling with the paracrine and autocrine activation of T cells, and complement proteins have also been implicated in shaping T cell fate by acting at the intracellular level, as extensively reviewed by Reis et al. (24). Another emerging feature of complement is the regulation of cell metabolism extending from adipocytes to liver and pancreas (25). Complement also modulates metabolic pathways in immune cells (26), suggesting that inflammation could be restrained by targeting of specific complement proteins. As a result, experimental studies have investigated complement in the immune modulation of diverse inflammatory diseases, including asthma, arthritis, and solid cancer (27–29).

In addition to cells traditionally considered part of the immune system, complement was also recently shown to interact with platelets, which are currently characterized as an innate immune cell (30). Accumulating data suggest that complement and platelets interact during the early cellular and molecular events that promote atherogenesis (31). Interestingly, signaling pathways between platelets and complement act on endothelial cells, affecting their pro-atherogenic features (32). These data suggest the potential involvement of complement in a wide spectrum of diseases associated with atherogenesis.

Complement and thrombosis

Complement and coagulation were once considered entirely independent pathways; however, it is now clear there is close interaction. Many of the key enzymes in both pathways are serine proteases. Complement-driven diseases, such as PNH, are characterized by a high thrombosis rate that is abrogated by complement inhibition, to the extent that anticoagulation is no longer needed (33).

The underlying mechanisms of complement-mediated thrombosis are not fully clarified, but thrombosis is a prominent clinical feature of all complementopathies. There are multiple proposed mechanisms of complement and thrombosis interactions, as thoroughly reviewed by Hill et al. (34). Direct interactions between complement and coagulation are mediated by C5a (35) and coagulation factors (i.e., thrombin, plasmin, and coagulation factors FXa and FXIa), which can activate complement (36–40). Thrombin was also recently shown to act as a potential C5a convertase in vitro, generating C5T and C5bT (41).

Indirect effects of complement on thrombosis have also been observed in hemolytic anemias (42). Recent evidence suggests that heme-induced thromboinflammation is significantly attenuated by C5 inhibition, with additional benefits observed when C5 inhibition is combined with an inhibitor of the TLR coreceptor CD14 (43). In addition, cholesterol crystals can induce coagulation activation via complement-mediated expression of tissue factor (44). This novel notion of thromboinflammation is expected to play a central role in a wide spectrum of disorders, ranging from thrombotic microangiopathies to autoimmune diseases (45).

Complement in disease

The inability to regulate complement drives the pathophysiology of a variety of diseases that cross multiple medical specialties. These disorders are often associated with specific mutations or autoantibodies that drive complement-mediated end-organ damage. Increasingly, pharmacologic complement inhibition of these pathways mitigates end-organ damage, which lays the foundation for precision medicine in complementopathies. Specific complement inhibitors at different sites of the complement cascade, similar to what exists in coagulation, will soon be widely available. Since these entities are diagnosed and treated by different medical specialties, this section of the Review will focus specifically on disease characteristics and diagnostic and therapeutic features that concern the complement cascade. Table 2 summarizes disorders in which complement inhibition has been shown to be beneficial.

Table 2

Disorders in which complement inhibition is beneficial

Hematology

Paroxysmal nocturnal hemoglobinuria

Complement activation. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder caused by somatic mutations in PIGA that lead to the absence of glycosylphosphatidylinositol-anchored (GPI-anchored) proteins on the surfaces of affected cells (33). Two of the missing GPI-anchored proteins (CD55 and CD59) are complement-regulatory proteins (46, 47). Because of their absence from erythrocyte membranes, hemolysis in PNH is primarily due to APC activation. Before 1990, diagnosis of PNH was based on the Ham, or acidified serum, test that was described in the 1930s (48). This test is based on the susceptibility of PNH cells to acidified serum, which serves as an APC activator (48). Thus, incubation of PNH erythrocytes with acidified serum leads to hemolysis that is not observed in normal erythrocytes. Today, PNH is diagnosed by flow cytometry. Fluoresceinated monoclonal antibodies against GPI-anchored proteins and/or fluorescein-labeled proaerolysin (FLAER) are used to detect the absence of GPI-anchored proteins from the surface of cells in peripheral blood (49, 50). Without therapy, the median survival is roughly 15–20 years; the leading cause of death is thrombosis, highlighting the important link between complement and thrombosis (51, 52).

Complement inhibition. Complement inhibition is the treatment of choice for PNH patients with severe hemolytic anemia and/or thrombosis. There are two FDA-approved drugs: eculizumab (approved in 2007) and ravulizumab (approved in 2019). Both monoclonal antibodies bind C5 and sterically hinder cleavage of C5 by the C5 convertase. This blocks the generation of the proinflammatory C5a molecule and MAC formation (53, 54). Ravulizumab has the advantage of 4-fold longer half-life, but otherwise the drugs are noninferior (55, 56). Recently, ravulizumab has shown sustained 1-year safety and efficacy (57), as well as decreased breakthrough hemolysis (58). Both drugs stop intravascular hemolysis, eliminate or reduce the need for blood transfusion, improve quality of life, and markedly attenuate the thrombosis risk. Ravulizumab is currently the drug of choice given its long half-life and more convenient dosing.

Terminal complement inhibition at C5 (downstream of CD55) in PNH usually results in mild to moderate extravascular hemolysis. This is because PNH red cells are also CD55 deficient, leading to unimpaired C3b opsonization and subsequent formation of C3 fragments that result in extravascular hemolysis in the liver and spleen (59). Moreover, complement-amplifying conditions (e.g., pregnancy, surgery, infections) can lead to a high density of surface C3b molecules that cause steric hindrance and decrease binding of eculizumab/ravulizumab to C5, ultimately causing breakthrough intravascular hemolysis (60). The only major adverse effect of C5 inhibition has been an expected increased risk of Neisseria meningitidis infection (0.5% risk annually) (61). The predictable toxicity from C5 inhibition and lack of other major end-organ toxicity are a testament to this precision medicine–based approach.

Novel complement inhibitors are in development, as summarized in Figure 1 (62–64). Among them, crovalimab is a subcutaneously administered monoclonal antibody that also targets C5 at a different epitope from eculizumab and ravulizumab. It is administered every 4 weeks and, in a phase I/II trial, was able to stop intravascular hemolysis in 10 treatment-naive PNH patients (65). Inhibition of targets upstream of both CD59 and CD55, such as C3, factor D, and factor B, is even more precise and can block intravascular and extravascular hemolysis because it blocks C3 fragment accumulation on red blood cells (RBCs). In an open-label phase II trial of treatment-naive patients, an oral factor D inhibitor (danicopan) resulted in hemoglobin improvement and elimination of intravascular hemolysis without evidence of C3-mediated extravascular hemolysis (66). In a separate study of 12 eculizumab-treated, transfusion-dependent PNH patients, danicopan was able to improve hemoglobin and eliminate the need for blood transfusions (67). In vitro studies suggest that danicopan preserves classical and lectin pathway activity against invasive pathogens (68). In addition, increased meningococcal killing in vaccinated volunteers has been observed in the presence of danicopan in contrast to anti-C5 inhibitors (69). Pegcetacoplan is a 15–amino acid cyclic peptide conjugated to polyethylene glycol that binds to C3 and prevents C3 and C5 cleavage by their respective convertases. In a phase Ib, open-label clinical study involving 6 transfusion-dependent, eculizumab-treated PNH patients, daily subcutaneous pegcetacoplan was well tolerated, improved hemoglobin, and stopped the need for transfusions (70). Thus, the treatment paradigm for PNH is likely to change toward a precision medicine model as these novel complement inhibitors enter the clinic.

Cold agglutinin disease

Complement activation. Cold agglutinins are autoantibodies (typically IgM) that agglutinate RBCs at 4°C but may also act at warmer temperatures. Cold agglutinin disease (CAD) is classified as either primary or secondary. Primary CAD is a clonal B cell lymphoproliferative disorder that is also called primary cold agglutinin–associated lymphoproliferative disease; it is distinct from lymphoplasmacytic lymphoma (MYD88 L265P negative), marginal zone lymphoma, and other low-grade lymphoproliferative diseases (71). Secondary CAD is a syndrome associated with a variety of infectious and neoplastic disorders (aggressive lymphomas, Hodgkin’s lymphoma, carcinomas, etc.). Hemolysis is driven by activation of the classical complement pathway, resulting in opsonization and predominantly extravascular hemolysis (72). Cold agglutinins with high thermal amplitude bind to erythrocytes in acral parts of the circulation and often have specificity for the I antigen on RBCs. The IgM cold agglutinin (IgM-CA) antibody activates the classical complement pathway. C1 esterase activates C4 and C2, ultimately generating the C3 convertase, which cleaves C3 to C3a and C3b. Upon return to warmer portions of the circulation (~37°C), the IgM-CA dissociates from the cell surface, but C3b remains bound to the RBC. The C3b-coated RBCs are then sequestered by macrophages of the reticuloendothelial system, predominantly in the liver (extravascular hemolysis). C3b of the surviving RBCs is eventually cleaved, leaving a high number of circulating RBCs with C3d on the surface. Patients with CAD have increased early mortality and a high risk of thromboembolism.

Complement inhibition. Rituximab is often used as initial therapy for CAD; it leads to remission (median duration 1 year) in roughly 50% of patients (73). Sutimlimab is a humanized monoclonal antibody that binds to C1s and inhibits classical complement activation (Figure 1). A recent phase Ib trial of sutimlimab in patients with CAD demonstrated that weekly intravenous dosing for 4 weeks followed by biweekly dosing thereafter rapidly aborted complement C1s–mediated hemolysis and significantly increased hemoglobin levels, precluding the need for RBC transfusions (74). All patients responded to sutimlimab within a few weeks, with a median rise in hemoglobin of almost 4 g/dL. Sutimlimab does not affect the production of cold agglutinins or their binding to RBC antigens; thus, CAD patients may still experience acrocyanosis.

More recently, results from the phase III trial of sutimlimab have demonstrated efficacy in primary endpoints (a composite of hemoglobin increase ≥ 2 g/dL or hemoglobin ≥ 12 g/dL at treatment assessment [average from weeks 23, 25, and 26] and transfusion avoidance from week 5 to week 26) and secondary endpoints (change from baseline in hemolytic markers and quality of life) (75). Thus, targeting of C1s with sutimlimab, a more precise target than CD20, will likely become standard therapy for CAD.

Nephrology

Atypical or complement-mediated hemolytic uremic syndrome

Complement activation. Atypical hemolytic uremic syndrome (aHUS) presents as a thrombotic microangiopathy (TMA) with the clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage (76) with preserved function of the disintegrin and metalloproteinase ADAMTS13. Among TMAs, aHUS has long served as an archetypal disease model of complement dysregulation. Recently, two published consensus documents have changed the terminology of TMAs from a model based on underlying disease to a pathophysiology-driven model (77, 78), introducing the term complement-mediated HUS (CM-HUS). The prevalent “two-hit” hypothesis for CM-HUS pathogenesis is that genetic or acquired (e.g., anti–complement factor H autoantibodies) defects in complement regulation shape a predisposing phenotype toward excessive complement activation. This complement phenotype is then coupled to a second hit that propagates complement amplification (79, 80). Complement-amplifying conditions are often infections, autoimmunity, surgery, pregnancy, or cancer.

CM-HUS–associated mutations cause either loss of function of complement-regulatory proteins, including complement factor H (CFH), complement factor I (CFI), thrombomodulin (THBD), and CD46/membrane cofactor protein (MCP), or gain of function of complement-activating proteins, including complement factor B (CFB) and C3 (81). Although THBD may also act as a complement regulator (82), further studies are needed to confirm the roles of coagulation pathway proteins (83). A recent study also revealed mutations in VTN, which encodes the terminal complement inhibitor vitronectin, in CM-HUS patients (84). The only mutations in this disease that are not associated with complement dysregulation are found in diacylglycerol kinase-ε (DGKE) (85, 86). Figure 2 summarizes mutations in these complement-related proteins. These germline variants in genes that regulate the APC are present in about 50% of patients with CM-HUS (87, 88). Factor H autoantibodies may also be found in up to 10% of CM-HUS (89). The majority of these patients lack CFHR1 and CFHR3, owing to homozygous deletion of the genomic region that expresses them (90). Sequencing results do not affect early treatment decisions given the acute presentation, the time it takes to get results, and the uncertainty regarding the relevance of some germline variants (91).

Traditional biomarkers used in clinical complement laboratories, such as hemolytic assays of classical and alternative pathway activity (CH-50 and AP-50, respectively) and ELISA of C3 concentration or APC activity (Wieslab), are not reliable for CM-HUS diagnosis (92). Soluble C5b-9 is not diagnostic for CM-HUS because values have a substantial overlap with other TMAs (93). Translational studies have also used C5b-9 deposition on endothelial cells to detect evidence of complement activation in patients with TMAs (94, 95). In vivo deposition of C5b-9 on dermal microvessels in the transplant setting has also been shown (96). In an effort to develop a rapid and reliable in vitro diagnostic assay for CM-HUS, the modified Ham test has been suggested, as described in Figure 3A (97). The latter can distinguish between CM-HUS and thrombotic thrombocytopenic purpura (TTP), but the assay is not yet available in clinical laboratories (97–99).

Complementopathies in the clinic.Figure 3

Complementopathies in the clinic. (A) Model of the modified Ham (mHam) test. PIGAnull (PNH-like) TF1 cells do not express CD55 and CD59 and are therefore susceptible to complement-mediated killing. Cells are incubated with patient and control sera, then with a WST-1 cell proliferation dye reagent (Roche). Nonviable cells do not release dye because of complement-mediated killing, resulting in differences in measured absorbance. The percentage of live cells is calculated as the ratio of sample absorbance relative to its heat-inactivated control, multiplied by 100. The percentage of nonviable cells is a measure of complement activation. (B) Proposed model for APS and CAPS. Recent studies suggest that aPLs induce complement activation in patients with complement-amplifying trigger(s), such as infection, surgery, or autoimmune disease, and cause thrombosis in APS. Patients who also have a pathogenic loss-of-function mutation in a complement-inhibitory factor (e.g., CFH, CFI, CD46, or THBD) or a gain-of-function mutation of a complement-activating factor (e.g., CFB, C3) are likely to be predisposed to uncontrolled complement activation. In the setting of a complement-amplifying trigger, aPL-induced complement activation could lead to disseminated thrombosis and ischemic multiorgan failure in CAPS. PIGA, phosphatidylinositol N-acetylglucosaminyltransferase subunit A; PNH, paroxysmal nocturnal hemoglobinuria; APS, antiphospholipid syndrome; CAPS, catastrophic antiphospholipid syndrome; aPL, antiphospholipid antibody.

Complement inhibition. CM-HUS is an urgent life-threatening syndrome requiring prompt initiation of therapy (100). The diagnosis is suspected in a patient with TMA who is Shiga toxin–negative with ADAMTS13 activity over 10%. Distinction between TTP and CM-HUS is important, as plasma exchange does not reliably arrest the complement-mediated organ damage occurring in CM-HUS (101). Improvements in platelet count and lactate dehydrogenase (LDH) are usually seen within days of eculizumab administration (102, 103). Kidney recovery may take several weeks to months (104). Eculizumab is administered intravenously every 7 days for the first 5 weeks and biweekly thereafter; however, the optimal duration of therapy is unclear (103, 105, 106). While early reports suggested that long-term/indefinite therapy is required, more recent reports suggest that eculizumab may be safely discontinued in many CM-HUS patients (107–109). Before eculizumab is discontinued, the patient should be in complete remission (normal platelet counts, LDH, and renal function) and potential complement-activating “triggers” should be controlled. In addition to the risk of meningitis mentioned in association with PNH, eculizumab hepatotoxicity has been reported in pediatric CM-HUS (110).

Glomerulopathies

Glomerulopathies consist of a wide range of diseases in the majority of which complement plays a central role. C3 glomerulopathy (C3G) is characterized by APC activation leading to C3 deposition in the glomeruli (111). Recent studies have found complement-related mutations in C3G, similar to those of CM-HUS. Interestingly, mutations in C3G cause different protein changes and, therefore, different phenotypes compared with CM-HUS mutations (112). These discoveries, along with experimental models of complement dysregulation (113), have prompted studies of complement inhibitors in these patients. Indeed, eculizumab has been administered in case reports and series of C3G transplant recipients (114–116). However, since the principal defect is caused by proximal complement activation, specific blockade is expected to show higher efficacy. Ongoing clinical trials are examining the efficacy of specific blockade in C3G with narsoplimab, sutimlimab, danicopan, and avacopan (Figure 1), all of which block complement activation more proximally. Apart from C3G, IgA nephropathy, lupus nephritis, and membranous nephropathy are also under study with complement inhibitors (117).

Obstetrics: HELLP syndrome

HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome usually arises in the third trimester of pregnancy and resolves shortly after delivery (118). Although its pathogenesis is not fully clear, endothelial dysfunction, partly mediated by complement, plays a central role. Fetal mortality approaches 30% when HELLP syndrome occurs early in the third trimester; maternal mortality may also approach 5% to 10%. Investigators have hypothesized that CM-HUS and HELLP syndrome may share a similar pathophysiology, because the clinical manifestations of hypertension, renal insufficiency, thrombocytopenia, elevated LDH, elevated aspartate aminotransterase, and even the presence of schistocytes are common to both disorders. Recent data using next-generation sequencing and functional complement assays in HELLP patients support this hypothesis (98, 99). Similar to CM-HUS, rare germline variants (variant allele frequency <1%) in genes regulating the APC (e.g., C3, CFH, CFB, MCP, etc.) and/or activation of complement using the modified Ham test are found in up to 50% of patients with HELLP syndrome (98, 99). These data suggest that, as with CM-HUS, a large subset of HELLP syndrome is driven by an inability to regulate complement. The thrombocytopenia is consumptive, the hemolysis is mechanical, and the elevated “liver function tests” (LDH, bilirubin, and aspartate aminotransferase) are actually markers of intravascular hemolysis rather than intrinsic liver dysfunction. Germline mutations in genes that regulate the APC may predispose to HELLP syndrome. Complement levels normally rise after the second trimester of pregnancy and may serve as a complement amplifier, along with other factors (autoimmunity, infection, etc.) that contribute to vascular damage (119, 120). Complement levels decrease following delivery, possibly explaining why the disease typically resolves postpartum. There are now several case reports describing the use of eculizumab to treat HELLP syndrome, but this is not an FDA-approved use of the drug (121).

Transplantation: transplant-associated thrombotic microangiopathy

Transplant-associated TMA (TA-TMA) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (HCT) (122). Although it manifests with the clinical triad of a TMA, diagnosis is largely hindered by the high incidence of cytopenias and organ dysfunction in HCT recipients. Current diagnostic criteria have been criticized for their diagnostic sensitivity (123). Moving the field forward, a growing number of genetic and functional data suggest increased complement activation in both the adult and pediatric population of TA-TMA (124–126). Soluble C5b-9 levels were also incorporated into recently proposed severity criteria of TA-TMA aiming to facilitate early diagnosis and treatment (127).

Eculizumab treatment is increasingly used to treat both adult and pediatric patients with TA-TMA (128–132). Despite high response rates to eculizumab treatment that reach 93%, overall survival remains low (~30%) in early reports from the adult population (130, 131). However, a recent study of 64 pediatric TA-TMA patients has shown an increased 1-year survival of 66% in eculizumab-treated patients compared with 17% in a historic control group (132). Several issues remain to be further investigated: timing of initiation, proper patient selection, dosing, and duration of therapy in patients with transplants. Interestingly, a novel C5 inhibitor, coversin, was successfully used in a TA-TMA patient with a C5 variant that caused resistance to eculizumab treatment (133). Recently, a phase II single-arm, open-label study of an inhibitor of the lectin pathway, the MASP-2 inhibitor OMS721/narsoplimab, in 19 TA-TMA patients also reported increased median overall survival in comparison with a historical control of conventional treatment (347 vs. 21 days from TA-TMA diagnosis) (134). As a result, a phase III clinical trial is ongoing (Table 2).

Rheumatology: antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is an acquired thrombophilia characterized by thrombosis affecting the venous or arterial vascular systems and/or obstetrical morbidity with the persistent presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibody, and anti–β2-glycoprotein-I (anti-β2GPI) (135). A severe form of APS characterized by widespread thrombosis and multi-organ failure developing over less than a week, termed catastrophic APS (CAPS), affects a subset (~1%) of APS patients. CAPS often presents as a TMA and has a fulminant course with more than 40% mortality despite the best available therapy (136, 137).

Complement activation has been shown in murine models of APS, suggesting a crucial role of complement in antiphospholipid antibody–mediated thrombosis (138–141) and obstetric (142–144) complications. Increased C5b-9 (145), Bb fragments, and C3a (146, 147) have been observed in APS sera (148). More recent data demonstrate that complement activation in APS is triggered by anti-β2GPI antibodies (149). A positive modified Ham test, as described in Figure 3A, was highly predictive for thrombotic events. Moreover, more than 50% of patients with CAPS harbor rare germline variants in complement-regulatory genes, similarly to CM-HUS and HELLP syndrome patients. This may explain the more severe CAPS phenotype, as demonstrated in Figure 3B (149). In line with these data, several reports have documented efficacy of eculizumab in refractory thrombotic APS (150) and CAPS (151–154). Finally, eculizumab prevented recurrence of APS and enabled renal transplantation in three APS patients (155). Thus, future studies of complement inhibition are indicated for severe forms of APS and CAPS.

Neurology

Myasthenia gravis

The majority of myasthenia gravis (MG) patients express acetylcholine receptor antibodies (AChR-Abs) (156). These antibodies bind C1q, activate the complement cascade, and ultimately lead to MAC generation. Initial evidence of complement activation in MG patients (157–160) has been confirmed in complement-deficient mouse models, suggesting a crucial role of MAC-mediating signals in MG (161–165). Complement was successfully targeted with passive and active experimental studies in MG (166). These data led to the phase III randomized double-blind placebo-controlled REGAIN trial in 125 patients with AChR-Ab–positive refractory generalized MG (167). Based on significant improvements in activities of daily living, muscle strength, and health-related quality of life, eculizumab received regulatory approval for treatment of these patients.

Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder of the central nervous system traditionally considered an autoimmune inflammatory disease and treated mainly with immunosuppressive agents such as rituximab (168). Antibodies against aquaporin-4 (AQP4) are found in the majority of patients (169, 170) and have been shown to activate complement in vitro and in vivo (171, 172). Complement-mediated death of neurons near astrocytes was mitigated by complement inhibition (173). In this context, upregulation of the complement regulator CD55 has reduced NMOSD pathology (174).

A phase II study of eculizumab in 14 patients has shown the potential of the drug to prevent relapses (175). These results have been confirmed in the most recent randomized, double-blind, time-to-event trial in 143 AQP4-positive patients (176). It should be noted, however, that eculizumab did not improve measures of disability progression, suggesting that long-term administration needs to be evaluated in light of two additional clinical trials of immunotherapeutic agents in patients with NMOSD (177).

Conclusion and future perspectives

Over the past few decades, our understanding of complement and precision medicine has evolved. Terminal complement inhibition is currently the mainstay of treatment for complement-mediated disorders, or complementopathies, across multiple medical specialties. Potentially novel indications span various disciplines, including hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology. Complement involvement has been speculated in a wide range of entities that have not been described in detail in this Review, such as age-related macular degeneration (178), hyperhemolysis syndrome (21), neurodegenerative diseases (62), periodontitis (179), and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis (180). Improvements in genetic and functional assays coupled with numerous novel and highly specific complement inhibitors will only increase the personalized approach to treating complementopathies.

Acknowledgments

Given the broad scope of this Review, the authors often refer to specialized review articles rather than primary literature, and they have been able to include only selected examples of original work in the field. Therefore, the authors thank colleagues who are not specifically cited for their contribution and their understanding. EG is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme (Human Resources Development, Education and Lifelong Learning 2014-2020) (MIS 5033021), enabled through the State Scholarships Foundation. RB received funding support from NIH/NHLBI R01HL133113.

Address correspondence to: Robert A. Brodsky, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1025, Baltimore, Maryland 21205, USA. Phone: 410.502.2546; Email: brodsro@jhmi.edu.

Footnotes

Conflict of interest: RAB is a member of the scientific advisory board for and receives grant funding from Alexion Pharmaceuticals Inc.

Copyright: © 2020, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2020;130(5):2152–2163.https://doi.org/10.1172/JCI136094.

References
  1. Collins FS. The human genome project and the future of medicine. Ann N Y Acad Sci. 1999;882:42–55.
    View this article via: PubMed CrossRef Google Scholar
  2. Joyner MJ, Paneth N. Promises, promises, and precision medicine. J Clin Invest. 2019;129(3):946–948.
    View this article via: JCI PubMed CrossRef Google Scholar
  3. Merrill SA, Brodsky RA. Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2018;2018(1):371–376.
    View this article via: PubMed Google Scholar
  4. Baines AC, Brodsky RA. Complementopathies. Blood Rev. 2017;31(4):213–223.
    View this article via: PubMed CrossRef Google Scholar
  5. Varela JC, Tomlinson S. Complement: an overview for the clinician. Hematol Oncol Clin North Am. 2015;29(3):409–427.
    View this article via: PubMed CrossRef Google Scholar
  6. Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058–1066.
    View this article via: PubMed CrossRef Google Scholar
  7. Harboe M, Mollnes TE. The alternative complement pathway revisited. J Cell Mol Med. 2008;12(4):1074–1084.
    View this article via: PubMed CrossRef Google Scholar
  8. Brunhouse R, Cebra JJ. Isotypes of IgG: comparison of the primary structures of three pairs of isotypes which differ in their ability to activate complement. Mol Immunol. 1979;16(11):907–917.
    View this article via: PubMed CrossRef Google Scholar
  9. Gewurz AT, Lint TF, Imherr SM, Garber SS, Gewurz H. Detection and analysis of inborn and acquired complement abnormalities. Clin Immunol Immunopathol. 1982;23(2):297–311.
    View this article via: PubMed CrossRef Google Scholar
  10. Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999;42(1–3):23–30.
    View this article via: PubMed CrossRef Google Scholar
  11. Preissner KT, Podack ER, Müller-Eberhard HJ. The membrane attack complex of complement: relation of C7 to the metastable membrane binding site of the intermediate complex C5b-7. J Immunol. 1985;135(1):445–451.
    View this article via: PubMed Google Scholar
  12. Cortes C, Ohtola JA, Saggu G, Ferreira VP. Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement. Front Immunol. 2012;3:412.
    View this article via: PubMed Google Scholar
  13. Pangburn MK, Müller-Eberhard HJ. Initiation of the alternative complement pathway due to spontaneous hydrolysis of the thioester of C3. Ann N Y Acad Sci. 1983;421:291–298.
    View this article via: PubMed CrossRef Google Scholar
  14. Chapitis J, Lepow IH. Multiple sedimenting species of properdin in human serum and interaction of purified properdin with the third component of complement. J Exp Med. 1976;143(2):241–257.
    View this article via: PubMed CrossRef Google Scholar
  15. Ferreira VP. Properdin. In: Barnum S, Schein T, eds. The Complement FactsBook. 2nd ed. London, United Kingdom: Elsevier; 2018:283–293.
  16. Neth O, Jack DL, Dodds AW, Holzel H, Klein NJ, Turner MW. Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect Immun. 2000;68(2):688–693.
    View this article via: PubMed CrossRef Google Scholar
  17. Saifuddin M, Hart ML, Gewurz H, Zhang Y, Spear GT. Interaction of mannose-binding lectin with primary isolates of human immunodeficiency virus type 1. J Gen Virol. 2000;81(pt 4):949–955.
    View this article via: PubMed Google Scholar
  18. Héja D, et al. Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2. Proc Natl Acad Sci U S A. 2012;109(26):10498–10503.
    View this article via: PubMed CrossRef Google Scholar
  19. Gavriilaki E, Brodsky RA. Complement-mediated coagulation disorders: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. In: Kitchens C, Kessler C, Konkle BA, Streiff MB, Garcia DA, eds. Consultative Hemostasis and Thrombosis. 4th ed. Philadelphia, Pennsylvania, USA: Elsevier; 2019:473–490.
    View this article via: PubMed Google Scholar
  20. Merle NS, Boudhabhay I, Leon J, Frémeaux-Bacchi V, Roumenina LT. Complement activation during intravascular hemolysis: Implication for sickle cell disease and hemolytic transfusion reactions. Transfus Clin Biol. 2019;26(2):116–124.
    View this article via: PubMed CrossRef Google Scholar
  21. Merrill SA, Brodsky RA, Lanzkron SM, Naik R. A case-control analysis of hyperhemolysis syndrome in adults and laboratory correlates of complement involvement. Transfusion. 2019;59(10):3129–3139.
    View this article via: PubMed CrossRef Google Scholar
  22. Eden A, Miller GW, Nussenzweig V. Human lymphocytes bear membrane receptors for C3b and C3d. J Clin Invest. 1973;52(12):3239–3242.
    View this article via: JCI PubMed CrossRef Google Scholar
  23. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271(5247):348–350.
    View this article via: PubMed CrossRef Google Scholar
  24. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019;19(8):503–516.
    View this article via: PubMed CrossRef Google Scholar
  25. Phieler J, Garcia-Martin R, Lambris JD, Chavakis T. The role of the complement system in metabolic organs and metabolic diseases. Semin Immunol. 2013;25(1):47–53.
    View this article via: PubMed CrossRef Google Scholar
  26. Geltink RIK, Kyle RL, Pearce EL. Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol. 2018;36:461–488.
    View this article via: PubMed CrossRef Google Scholar
  27. Lajoie S, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010;11(10):928–935.
    View this article via: PubMed CrossRef Google Scholar
  28. Hashimoto M, et al. Complement drives Th17 cell differentiation and triggers autoimmune arthritis. J Exp Med. 2010;207(6):1135–1143.
    View this article via: PubMed CrossRef Google Scholar
  29. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–797.
    View this article via: PubMed CrossRef Google Scholar
  30. Eriksson O, Mohlin C, Nilsson B, Ekdahl KN. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol. 2019;10:1590.
    View this article via: PubMed Google Scholar
  31. Patzelt J, Verschoor A, Langer HF. Platelets and the complement cascade in atherosclerosis. Front Physiol. 2015;6:49.
    View this article via: PubMed Google Scholar
  32. Speth C, et al. Complement and platelets: mutual interference in the immune network. Mol Immunol. 2015;67(1):108–118.
    View this article via: PubMed CrossRef Google Scholar
  33. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811.
    View this article via: PubMed CrossRef Google Scholar
  34. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985–4996.
    View this article via: PubMed CrossRef Google Scholar
  35. Ritis K, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006;177(7):4794–4802.
    View this article via: PubMed CrossRef Google Scholar
  36. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8(10):776–787.
    View this article via: PubMed CrossRef Google Scholar
  37. Clark A, et al. Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Mol Immunol. 2008;45(11):3125–3132.
    View this article via: PubMed CrossRef Google Scholar
  38. Amara U, et al. Molecular intercommunication between the complement and coagulation systems. J Immunol. 2010;185(9):5628–5636.
    View this article via: PubMed CrossRef Google Scholar
  39. Leung LL, Morser J. Plasmin as a complement C5 convertase. EBioMedicine. 2016;5:20–21.
    View this article via: PubMed CrossRef Google Scholar
  40. Huber-Lang M, et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med. 2006;12(6):682–687.
    View this article via: PubMed CrossRef Google Scholar
  41. Krisinger MJ, et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood. 2012;120(8):1717–1725.
    View this article via: PubMed CrossRef Google Scholar
  42. Chapin J, Terry HS, Kleinert D, Laurence J. The role of complement activation in thrombosis and hemolytic anemias. Transfus Apher Sci. 2016;54(2):191–198.
    View this article via: PubMed CrossRef Google Scholar
  43. Thomas AM, et al. Complement component C5 and TLR molecule CD14 mediate heme-induced thromboinflammation in human blood. J Immunol. 2019;203(6):1571–1578.
    View this article via: PubMed CrossRef Google Scholar
  44. Gravastrand CS, et al. Cholesterol crystals induce coagulation activation through complement-dependent expression of monocytic tissue factor. J Immunol. 2019;203(4):853–863.
    View this article via: PubMed CrossRef Google Scholar
  45. Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019;133(9):906–918.
    View this article via: PubMed CrossRef Google Scholar
  46. Lublin DM, Atkinson JP. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol. 1989;7:35–58.
    View this article via: PubMed CrossRef Google Scholar
  47. Rollins SA, Sims PJ. The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9. J Immunol. 1990;144(9):3478–3483.
    View this article via: PubMed Google Scholar
  48. Ham TH, Dingle JH. Studies on destruction of red blood cells. II. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: certain immunological aspects of the hemolytic mechanism with special reference to serum complement. J Clin Invest. 1939;18(6):657–672.
    View this article via: JCI PubMed CrossRef Google Scholar
  49. Brodsky RA, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. 2000;114(3):459–466.
    View this article via: PubMed CrossRef Google Scholar
  50. Borowitz MJ, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2010;78(4):211–230.
    View this article via: PubMed Google Scholar
  51. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol. 2004;126(1):133–138.
    View this article via: PubMed CrossRef Google Scholar
  52. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333(19):1253–1258.
    View this article via: PubMed CrossRef Google Scholar
  53. Hillmen P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355(12):1233–1243.
    View this article via: PubMed CrossRef Google Scholar
  54. Brodsky RA, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840–1847.
    View this article via: PubMed CrossRef Google Scholar
  55. Kulasekararaj AG, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540–549.
    View this article via: PubMed CrossRef Google Scholar
  56. Lee JW, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133(6):530–539.
    View this article via: PubMed CrossRef Google Scholar
  57. Kulasekararaj AH, et al. One-year efficacy and safety from a phase 3 trial of ravulizumab in adult patients with paroxysmal nocturnal hemoglobinuria receiving prior eculizumab treatment. Blood. 2019;134(suppl 1):2231.
    View this article via: PubMed Google Scholar
  58. Brodsky RA, et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. [published online ahead of print January 16, 2020]. Haematologica. https://doi.org/10.3324/haematol.2019.236877.
    View this article via: PubMed CrossRef Google Scholar
  59. Risitano AM, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113(17):4094–4100.
    View this article via: PubMed CrossRef Google Scholar
  60. Harder MJ, et al. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood. 2017;129(8):970–980.
    View this article via: PubMed CrossRef Google Scholar
  61. Winthrop KL, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018;24(suppl 2):S21–S40.
    View this article via: PubMed Google Scholar
  62. Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015;14(12):857–877.
    View this article via: PubMed CrossRef Google Scholar
  63. Ricklin D, Mastellos DC, Reis ES, Lambris JD. The renaissance of complement therapeutics. Nat Rev Nephrol. 2018;14(1):26–47.
    View this article via: PubMed CrossRef Google Scholar
  64. Mastellos DC, Reis ES, Yancopoulou D, Risitano AM, Lambris JD. Expanding complement therapeutics for the treatment of paroxysmal nocturnal hemoglobinuria. Semin Hematol. 2018;55(3):167–175.
    View this article via: PubMed CrossRef Google Scholar
  65. Röth A, et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135(12):912–920.
    View this article via: PubMed CrossRef Google Scholar
  66. Risitano AL, et al. Mechanistic evaluation of efficacy using biomarkers of the oral, small molecule factor d inhibitor, danicopan (ACH-4471), in untreated patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2019;134(suppl 1):2226.
    View this article via: PubMed Google Scholar
  67. Kulasekararaj AR, et al. A phase 2 open-label study of danicopan (ACH‑0144471) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to eculizumab monotherapy. Blood. 2019;134(suppl 1):3514.
    View this article via: CrossRef Google Scholar
  68. Kumar CG, Sujitha P. Kocuran, an exopolysaccharide isolated from Kocuria rosea strain BS-1 and evaluation of its in vitro immunosuppression activities. Enzyme Microb Technol. 2014;55:113–120.
    View this article via: PubMed CrossRef Google Scholar
  69. Konar M, Granoff DM. Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults. Blood. 2017;130(7):891–899.
    View this article via: PubMed CrossRef Google Scholar
  70. Wong RSM. Inhibition of C3 with APL-2 results in normalisation of markers of intravascular and extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2018;132(suppl 1):2314.
    View this article via: PubMed Google Scholar
  71. Randen U, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497–504.
    View this article via: PubMed CrossRef Google Scholar
  72. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023–2027.
    View this article via: PubMed CrossRef Google Scholar
  73. Berentsen S, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103(8):2925–2928.
    View this article via: PubMed CrossRef Google Scholar
  74. Jäger U, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893–901.
    View this article via: PubMed CrossRef Google Scholar
  75. Röth A, et al. Inhibition of complement C1s with sutimlimab in patients with cold agglutinin disease (CAD): results from the phase 3 Cardinal Study. Blood. 2019;134(suppl 2):LBA-2.
    View this article via: CrossRef Google Scholar
  76. Gavriilaki E, Anagnostopoulos A, Mastellos DC. Complement in thrombotic microangiopathies: unraveling Ariadne’s thread into the labyrinth of complement therapeutics. Front Immunol. 2019;10:337.
    View this article via: PubMed Google Scholar
  77. Loirat C, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31(1):15–39.
    View this article via: PubMed CrossRef Google Scholar
  78. Scully M. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017;15(2):312–322.
    View this article via: PubMed CrossRef Google Scholar
  79. May O, et al. Heme drives susceptibility of glomerular endothelium to complement overactivation due to inefficient upregulation of heme oxygenase-1. Front Immunol. 2018;9:3008.
    View this article via: PubMed Google Scholar
  80. Nester CM, et al. Atypical aHUS: state of the art. Mol Immunol. 2015;67(1):31–42.
    View this article via: PubMed CrossRef Google Scholar
  81. Rodríguez de Córdoba S, Hidalgo MS, Pinto S, Tortajada A. Genetics of atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost. 2014;40(4):422–430.
    View this article via: PubMed CrossRef Google Scholar
  82. Delvaeye M, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(4):345–357.
    View this article via: PubMed CrossRef Google Scholar
  83. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390(10095):681–696.
    View this article via: PubMed CrossRef Google Scholar
  84. Bu F, et al. Genetic analysis of 400 patients refines understanding and implicates a new gene in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2018;29(12):2809–2819.
    View this article via: PubMed CrossRef Google Scholar
  85. Lemaire M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45(5):531–536.
    View this article via: PubMed CrossRef Google Scholar
  86. Bruneau S, et al. Loss of DGKε induces endothelial cell activation and death independently of complement activation. Blood. 2015;125(6):1038–1046.
    View this article via: PubMed CrossRef Google Scholar
  87. Bresin E, et al. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol. 2013;24(3):475–486.
    View this article via: PubMed CrossRef Google Scholar
  88. Noris M, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5(10):1844–1859.
    View this article via: PubMed CrossRef Google Scholar
  89. Brocklebank V, et al. Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland. Kidney Int. 2017;92(5):1261–1271.
    View this article via: PubMed CrossRef Google Scholar
  90. Bhattacharjee A, et al. The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease. J Biol Chem. 2015;290(15):9500–9510.
    View this article via: PubMed CrossRef Google Scholar
  91. Brodsky RA. Complement in hemolytic anemia. Blood. 2015;126(22):2459–2465.
    View this article via: PubMed CrossRef Google Scholar
  92. Sperati CJ, Moliterno AR. Thrombotic microangiopathy: focus on atypical hemolytic uremic syndrome. Hematol Oncol Clin North Am. 2015;29(3):541–559.
    View this article via: PubMed CrossRef Google Scholar
  93. Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood. 2014;123(24):3733–3738.
    View this article via: PubMed CrossRef Google Scholar
  94. Timmermans SAMEG, et al. C5b9 formation on endothelial cells reflects complement defects among patients with renal thrombotic microangiopathy and severe hypertension. J Am Soc Nephrol. 2018;29(8):2234–2243.
    View this article via: PubMed CrossRef Google Scholar
  95. Galbusera M, et al. An ex vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome. Am J Kidney Dis. 2019;74(1):56–72.
    View this article via: PubMed CrossRef Google Scholar
  96. Chapin J, Shore T, Forsberg P, Desman G, Van Besien K, Laurence J. Hematopoietic transplant-associated thrombotic microangiopathy: case report and review of diagnosis and treatments. Clin Adv Hematol Oncol. 2014;12(9):565–573.
    View this article via: PubMed Google Scholar
  97. Gavriilaki E, et al. Modified Ham test for atypical hemolytic uremic syndrome. Blood. 2015;125(23):3637–3646.
    View this article via: PubMed CrossRef Google Scholar
  98. Vaught AJ, et al. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp Hematol. 2016;44(5):390–398.
    View this article via: PubMed CrossRef Google Scholar
  99. Vaught AJ, et al. Germline mutations in the alternative pathway of complement predispose to HELLP syndrome. JCI Insight. 2018;3(6):99128.
    View this article via: JCI Insight PubMed Google Scholar
  100. Gavriilaki E, Gkaliagkousi E, Grigoriadis S, Anyfanti P, Douma S, Anagnostopoulos A. Hypertension in hematologic malignancies and hematopoietic cell transplantation: an emerging issue with the introduction of novel treatments. Blood Rev. 2019;35:51–58.
    View this article via: PubMed CrossRef Google Scholar
  101. Caprioli J, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108(4):1267–1279.
    View this article via: PubMed CrossRef Google Scholar
  102. Legendre CM, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169–2181.
    View this article via: PubMed CrossRef Google Scholar
  103. Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open. 2013;3(11):e003573.
    View this article via: PubMed CrossRef Google Scholar
  104. Walle JV, Delmas Y, Ardissino G, Wang J, Kincaid JF, Haller H. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. J Nephrol. 2017;30(1):127–134.
    View this article via: PubMed CrossRef Google Scholar
  105. Greenbaum LA, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701–711.
    View this article via: PubMed CrossRef Google Scholar
  106. Licht C, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015;87(5):1061–1073.
    View this article via: PubMed CrossRef Google Scholar
  107. Merrill SA, Brittingham ZD, Yuan X, Moliterno AR, Sperati CJ, Brodsky RA. Eculizumab cessation in atypical hemolytic uremic syndrome. Blood. 2017;130(3):368–372.
    View this article via: PubMed CrossRef Google Scholar
  108. Ardissino G, et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis. 2014;64(4):633–637.
    View this article via: PubMed CrossRef Google Scholar
  109. Macia M, et al. Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome. Clin Kidney J. 2017;10(3):310–319.
    View this article via: PubMed Google Scholar
  110. Hayes W, Tschumi S, Ling SC, Feber J, Kirschfink M, Licht C. Eculizumab hepatotoxicity in pediatric aHUS. Pediatr Nephrol. 2015;30(5):775–781.
    View this article via: PubMed CrossRef Google Scholar
  111. Nester CM, Smith RJ. Complement inhibition in C3 glomerulopathy. Semin Immunol. 2016;28(3):241–249.
    View this article via: PubMed CrossRef Google Scholar
  112. Osborne AJ, et al. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J Immunol. 2018;200(7):2464–2478.
    View this article via: PubMed CrossRef Google Scholar
  113. Pickering MC, et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet. 2002;31(4):424–428.
    View this article via: PubMed CrossRef Google Scholar
  114. Regunathan-Shenk R, et al. Kidney transplantation in C3 glomerulopathy: a case series. Am J Kidney Dis. 2019;73(3):316–323.
    View this article via: PubMed CrossRef Google Scholar
  115. Garg N, et al. C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab. Nephrol Dial Transplant. 2018;33(12):2260–2265.
    View this article via: PubMed CrossRef Google Scholar
  116. Gurkan S, Fyfe B, Weiss L, Xiao X, Zhang Y, Smith RJ. Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol. 2013;28(10):1975–1981.
    View this article via: PubMed CrossRef Google Scholar
  117. Tortajada A, Gutierrez E, Pickering MC, Praga Terente M, Medjeral-Thomas N. The role of complement in IgA nephropathy. Mol Immunol. 2019;114:123–132.
    View this article via: PubMed CrossRef Google Scholar
  118. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol. 1982;142(2):159–167.
    View this article via: PubMed CrossRef Google Scholar
  119. Richani K, et al. Normal pregnancy is characterized by systemic activation of the complement system. J Matern Fetal Neonatal Med. 2005;17(4):239–245.
    View this article via: PubMed CrossRef Google Scholar
  120. Derzsy Z, Prohászka Z, Rigó J, Füst G, Molvarec A. Activation of the complement system in normal pregnancy and preeclampsia. Mol Immunol. 2010;47(7-8):1500–1506.
    View this article via: PubMed CrossRef Google Scholar
  121. Sarno L, Tufano A, Maruotti GM, Martinelli P, Balletta MM, Russo D. Eculizumab in pregnancy: a narrative overview. J Nephrol. 2019;32(1):17–25.
    View this article via: PubMed CrossRef Google Scholar
  122. Gavriilaki E, Sakellari I, Anagnostopoulos A, Brodsky RA. Transplant-associated thrombotic microangiopathy: opening Pandora’s box. Bone Marrow Transplant. 2017;52(10):1355–1360.
    View this article via: PubMed CrossRef Google Scholar
  123. Kennedy GA, Bleakley S, Butler J, Mudie K, Kearey N, Durrant S. Posttransplant thrombotic microangiopathy: sensitivity of proposed new diagnostic criteria. Transfusion. 2009;49(9):1884–1889.
    View this article via: PubMed CrossRef Google Scholar
  124. Jodele S, et al. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood. 2013;122(12):2003–2007.
    View this article via: PubMed CrossRef Google Scholar
  125. Gavriilaki E, et al. Linking complement activation, coagulation, and neutrophils in transplant-associated thrombotic microangiopathy. Thromb Haemost. 2019;119(9):1433–1440.
    View this article via: PubMed CrossRef Google Scholar
  126. Gavriilaki E, et al. Pretransplant genetic susceptibility: Clinical relevance in transplant-associated thrombotic microangiopathy. [published online ahead of print March 4, 2020]. Thromb Haemost. https://doi.org/10.1055/s-0040-1702225.
    View this article via: PubMed Google Scholar
  127. Jodele S, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124(4):645–653.
    View this article via: PubMed CrossRef Google Scholar
  128. Jodele S, et al. Terminal complement blockade after hematopoietic stem cell transplantation is safe without meningococcal vaccination. Biol Blood Marrow Transplant. 2016;22(7):1337–1340.
    View this article via: PubMed CrossRef Google Scholar
  129. Vasu S, et al. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2016;51(9):1241–1244.
    View this article via: PubMed CrossRef Google Scholar
  130. de Fontbrune FS, et al. Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation. 2015;99(9):1953–1959.
    View this article via: PubMed CrossRef Google Scholar
  131. Bohl SR, et al. Thrombotic microangiopathy after allogeneic stem cell transplantation: a comparison of eculizumab therapy and conventional therapy. Biol Blood Marrow Transplant. 2017;23(12):2172–2177.
    View this article via: PubMed CrossRef Google Scholar
  132. Jodele S, et al. Complement blockade for TA-TMA: lessons learned from large pediatric cohort treated with eculizumab. [published online ahead of print January 13, 2020]. Blood. https://doi.org/10.1182/blood.2019004218.
    View this article via: PubMed CrossRef Google Scholar
  133. Goodship THJ, et al. Use of the complement inhibitor Coversin to treat HSCT-associated TMA. Blood Adv. 2017;1(16):1254–1258.
    View this article via: PubMed CrossRef Google Scholar
  134. Rambaldi A, et al. Improved survival following OMS721 treatment of hematopoieic stem cell transplant-associated thrombotic microangiopathy (HCT-TMA). Paper presented at: 23rd Congress of the European Hematology Association; June 14–17, 2018; Stockholm, Sweden. http://library.ehaweb.org/eha/2018/stockholm/215162/alessandro.rambaldi.improved.survival.following.oms721.treatment.of.html Updated June 15, 2018. Accessed March 9, 2020.
  135. Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.
    View this article via: PubMed CrossRef Google Scholar
  136. Cervera R, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74(6):1011–1018.
    View this article via: PubMed CrossRef Google Scholar
  137. Cervera R, Espinosa G. Update on the catastrophic antiphospholipid syndrome and the “CAPS Registry.”. Semin Thromb Hemost. 2012;38(4):333–338.
    View this article via: PubMed CrossRef Google Scholar
  138. Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52(7):2120–2124.
    View this article via: PubMed CrossRef Google Scholar
  139. Carrera-Marín A, et al. C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. Lupus. 2012;21(14):1497–1505.
    View this article via: PubMed CrossRef Google Scholar
  140. Fischetti F, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005;106(7):2340–2346.
    View this article via: PubMed CrossRef Google Scholar
  141. Agostinis C, et al. A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood. 2014;123(22):3478–3487.
    View this article via: PubMed CrossRef Google Scholar
  142. Girardi G, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644–1654.
    View this article via: JCI PubMed CrossRef Google Scholar
  143. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10(11):1222–1226.
    View this article via: PubMed CrossRef Google Scholar
  144. Redecha P, et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood. 2007;110(7):2423–2431.
    View this article via: PubMed CrossRef Google Scholar
  145. Davis WD, Brey RL. Antiphospholipid antibodies and complement activation in patients with cerebral ischemia. Clin Exp Rheumatol. 1992;10(5):455–460.
    View this article via: PubMed Google Scholar
  146. Breen KA, Seed P, Parmar K, Moore GW, Stuart-Smith SE, Hunt BJ. Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome. Thromb Haemost. 2012;107(3):423–429.
    View this article via: PubMed CrossRef Google Scholar
  147. Devreese KM, Hoylaerts MF. Is there an association between complement activation and antiphospholipid antibody-related thrombosis? Thromb Haemost. 2010;104(6):1279–1281.
    View this article via: PubMed Google Scholar
  148. Chaturvedi S, Brodsky RA, McCrae KR. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol. 2019;10:449.
    View this article via: PubMed Google Scholar
  149. Chaturvedi S, et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020;135(4):239–251.
    View this article via: PubMed CrossRef Google Scholar
  150. Meroni PL, et al. Complement activation in antiphospholipid syndrome and its inhibition to prevent rethrombosis after arterial surgery. Blood. 2016;127(3):365–367.
    View this article via: PubMed CrossRef Google Scholar
  151. Shapira I, Andrade D, Allen SL, Salmon JE. Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum. 2012;64(8):2719–2723.
    View this article via: PubMed CrossRef Google Scholar
  152. Wig S, Chan M, Thachil J, Bruce I, Barnes T. A case of relapsing and refractory catastrophic anti-phospholipid syndrome successfully managed with eculizumab, a complement 5 inhibitor. Rheumatology (Oxford). 2016;55(2):382–384.
    View this article via: PubMed CrossRef Google Scholar
  153. Zikos TA, Sokolove J, Ahuja N, Berube C. Eculizumab induces sustained remission in a patient with refractory primary catastrophic antiphospholipid syndrome. J Clin Rheumatol. 2015;21(6):311–313.
    View this article via: PubMed CrossRef Google Scholar
  154. Strakhan M, Hurtado-Sbordoni M, Galeas N, Bakirhan K, Alexis K, Elrafei T. 36-year-old female with catastrophic antiphospholipid syndrome treated with eculizumab: a case report and review of literature. Case Rep Hematol. 2014;2014:704371.
    View this article via: PubMed Google Scholar
  155. Lonze BE, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant. 2014;14(2):459–465.
    View this article via: PubMed CrossRef Google Scholar
  156. Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis — autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016;12(5):259–268.
    View this article via: PubMed Google Scholar
  157. Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann N Y Acad Sci. 1987;505:326–332.
    View this article via: PubMed CrossRef Google Scholar
  158. Fazekas A, Komoly S, Bózsik B, Szobor A. Myasthenia gravis: demonstration of membrane attack complex in muscle end-plates. Clin Neuropathol. 1986;5(2):78–83.
    View this article via: PubMed Google Scholar
  159. Basta M, Illa I, Dalakas MC. Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barré syndrome, myasthenia gravis and dermatomyositis. J Neuroimmunol. 1996;71(1–2):227–229.
    View this article via: PubMed Google Scholar
  160. Romi F, Kristoffersen EK, Aarli JA, Gilhus NE. The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo. J Neuroimmunol. 2005;158(1–2):191–194.
    View this article via: PubMed Google Scholar
  161. Tüzün E, Scott BG, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. J Immunol. 2003;171(7):3847–3854.
    View this article via: PubMed CrossRef Google Scholar
  162. Chamberlain-Banoub J, Neal JW, Mizuno M, Harris CL, Morgan BP. Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats. Clin Exp Immunol. 2006;146(2):278–286.
    View this article via: PubMed CrossRef Google Scholar
  163. Lin F, Kaminski HJ, Conti-Fine BM, Wang W, Richmonds C, Medof ME. Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection. J Clin Invest. 2002;110(9):1269–1274.
    View this article via: JCI PubMed CrossRef Google Scholar
  164. Morgan BP, Chamberlain-Banoub J, Neal JW, Song W, Mizuno M, Harris CL. The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice. Clin Exp Immunol. 2006;146(2):294–302.
    View this article via: PubMed CrossRef Google Scholar
  165. Kusner LL, Halperin JA, Kaminski HJ. Cell surface complement regulators moderate experimental myasthenia gravis pathology. Muscle Nerve. 2013;47(1):33–40.
    View this article via: PubMed CrossRef Google Scholar
  166. Chamberlain JL, Huda S, Whittam DH, Matiello M, Morgan BP, Jacob A. Role of complement and potential of complement inhibitors in myasthenia gravis and neuromyelitis optica spectrum disorders: a brief review. [published online ahead of print September 3, 2019]. J Neurol. https://doi.org/10.1007/s00415-019-09498-4.
    View this article via: CrossRef PubMed Google Scholar
  167. Howard JF, 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):976–986.
    View this article via: PubMed CrossRef Google Scholar
  168. Kessler RA, Mealy MA, Levy M. Treatment of neuromyelitis optica spectrum disorder: acute, preventive, and symptomatic. Curr Treat Options Neurol. 2016;18(1):2.
    View this article via: PubMed CrossRef Google Scholar
  169. Jiao Y, et al. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology. 2013;81(14):1197–1204.
    View this article via: PubMed CrossRef Google Scholar
  170. Waters P, et al. Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2016;87(9):1005–1015.
    View this article via: PubMed CrossRef Google Scholar
  171. Hinson SR, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A. 2012;109(4):1245–1250.
    View this article via: PubMed CrossRef Google Scholar
  172. Saadoun S, Waters P, Bell BA, Vincent A, Verkman AS, Papadopoulos MC. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain. 2010;133(pt 2):349–361.
    View this article via: PubMed Google Scholar
  173. Duan T, Smith AJ, Verkman AS. Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica. J Neuroinflammation. 2018;15(1):294.
    View this article via: PubMed CrossRef Google Scholar
  174. Tradtrantip L, Duan T, Yeaman MR, Verkman AS. CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica. J Neuroinflammation. 2019;16(1):57.
    View this article via: PubMed CrossRef Google Scholar
  175. Pittock SJ, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013;12(6):554–562.
    View this article via: PubMed CrossRef Google Scholar
  176. Pittock SJ, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614–625.
    View this article via: PubMed CrossRef Google Scholar
  177. Collongues N, Ayme-Dietrich E, Monassier L, de Seze J. Pharmacotherapy for neuromyelitis optica spectrum disorders: current management and future options. Drugs. 2019;79(2):125–142.
    View this article via: PubMed CrossRef Google Scholar
  178. Yehoshua Z, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693–701.
    View this article via: PubMed CrossRef Google Scholar
  179. Hajishengallis G, et al. Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin Immunol. 2016;28(3):285–291.
    View this article via: PubMed CrossRef Google Scholar
  180. Chen M, Jayne DRW, Zhao MH. Complement in ANCA-associated vasculitis: mechanisms and implications for management. Nat Rev Nephrol. 2017;13(6):359–367.
    View this article via: PubMed CrossRef Google Scholar
Version history
  • Version 1 (April 20, 2020): Electronic publication
  • Version 2 (May 1, 2020): Print issue publication

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Introduction
  • Current understanding of complement biology for the clinician
  • Insights into complement potentially applicable to clinical practice
  • Complement in disease
  • Hematology
  • Nephrology
  • Obstetrics: HELLP syndrome
  • Transplantation: transplant-associated thrombotic microangiopathy
  • Rheumatology: antiphospholipid antibody syndrome
  • Neurology
  • Conclusion and future perspectives
  • Acknowledgments
  • Footnotes
  • References
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts