ABSTRACT
The complement system is a central component of the innate immune system, and it is a bridge to the adaptive immune system. With this broad functional reach, dysregulation of this system contributes to a wide range of inflammatory and autoimmune conditions. Drugs that inhibit the complement system have dramatically improved outcomes in many previously untreatable diseases, and the number of approved indications is growing rapidly, requiring specialists and generalists alike to be familiar with these drugs.
Complement is critical for proper immune surveillance and activation of the immune response.
Chronic, inappropriate, and uncontrolled complement activation can be associated with inflammatory diseases.
Complement inhibitors are already used in many medical specialties, and their indications are rapidly expanding. As these treatments become more common, clinicians will need to be acquainted with their indications and side effects.
Complement inhibitors increase the risk of infections with encapsulated organisms, particularly meningococci, requiring close monitoring, vaccinations, and prophylactic antibiotics.
The complement system, like the Krebs cycle, is something many physicians studied in school and then quickly forgot because it had limited clinical relevance in routine practice. However, as our understanding of the pathophysiologic basis of diseases has advanced, the roles of the complement system’s various elements have become more apparent across a wide spectrum of diseases.
See related editorial, page 237
In the past few years, several complement inhibitors have received US Food and Drug Administration (FDA) approval for a variety of indications, reshaping management algorithms for numerous diseases. As these medications enter the mainstream and with more on the way, understanding the complement system and the benefits and risks of therapeutic blockade has become crucial for optimal patient care.
Here, we provide a brief overview of the complement system and its role in the pathophysiology of a variety of diseases. We then highlight how complement inhibition has emerged as a revolutionary therapeutic strategy with current and future FDA approvals. We finally discuss important considerations for patients receiving these drugs, emphasizing the risk of infections.
OLD DISEASES, NEW THERAPEUTIC HORIZONS
A 31-year-old man who has been healthy until now is being evaluated for microscopic hematuria and proteinuria. His estimated glomerular filtration rate is 83 mL/min/m2, indicating stage 2 chronic kidney disease. Urine sediment analysis reveals dysmorphic red blood cells, and his urine protein-to-creatinine ratio is elevated at 1.5 g/g. Immune serologic workup is unrevealing, including normal C3 and C4 levels.
He undergoes a kidney biopsy, which shows mesangial hypercellularity in most sampled glomeruli, focal endocapillary hypercellularity, and segmental glomerulosclerosis in 2 glomeruli. One glomerular crescent is also seen. Tubular atrophy and interstitial fibrosis are minimal. Immunofluorescence reveals intense mesangial immunoglobulin (Ig) A and C3 staining.
This is a classic case of IgA nephropathy with predominantly inflammatory lesions on the kidney biopsy. Until recently, the only immunomodulatory options for treating it were systemic glucocorticoids, for which trials showed variable efficacy but an unequivocally increased risk of infections and death. Given the uncertain risks and benefits of steroids, treatment of IgA nephropathy varied: some clinicians gave them, others didn’t, giving only nonimmunomodulatory, antiproteinuric drugs such as renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter 2 inhibitors, particularly for patients who had preserved kidney function without nephrotic syndrome.
Neither of these approaches was wrong, given the limited options at the time! The 2021 Kidney Disease Improving Global Outcomes guideline,1 currently undergoing a much-needed update with other recently approved medications, supported both approaches and emphasized careful patient selection and risk-benefit discussion when contemplating systemic steroid therapy for IgA nephropathy.
IgA nephropathy is but one of many inflammatory diseases that had limited therapeutic options, while progressive damage accrued over years of uncontrolled disease.2 Experts would advocate for immunomodulatory therapy in such scenarios if a safe and effective option was available. Until recently, such an option was not available, but fortunately, things are rapidly changing.
Complement inhibitors have been a major breakthrough, offering an effective steroid-sparing approach for patients with inflammatory disease. In the past 3 years alone, 3 medications received FDA approval for treating IgA nephropathy, and many more are on the horizon. Iptacopan, a factor B inhibitor, backed by promising efficacy and safety data, received accelerated FDA approval for IgA nephropathy in late 2023.3
In this review, we do not aim to do a deep dive into the pathophysiology and management of IgA nephropathy, or any of the other renal or nonrenal conditions in which complement-inhibiting therapy is currently used. Instead, we hope to highlight the previously underappreciated and unrecognized role of the complement system in many diseases and how complement inhibitors can revolutionize (and in some cases already have revolutionized) their management.
THREE PATHWAYS THAT CONVERGE ON C3 AND THEN C5
Our understanding of the complement system has advanced tremendously since complement was first described in the 19th century as a heat-labile factor that complemented the function of a heat-stable factor (antibodies), although the terms complement and antibodies would not be coined until many years after.4,5 Over 50 unique proteins have been identified in the complement cascade.
Complement is a surveillance mechanism, constantly keeping watch against a broad array of “foreign” threats, nonspecifically labeling them, engaging effector immune cells, and recruiting additional complement proteins to eliminate said threats.6 Thus, it has canonical functions in the innate immune system and in mediating adaptive immune system activation. It also has noncanonical functions that are beyond the scope of this review.
Complement activation can occur via any of 3 pathways (Figure 1):
Targeted recognition of antibodies (IgG or IgM) in the classical pathway
Direct recognition of pathogen-associated molecular patterns in the lectin pathway
Spontaneous activity in the alternative pathway.
Complexities in complement activation open opportunities for therapeutic inhibition. Activation of complement occurs in response to a diverse range of triggers, leading to formation of different isoforms of C3 convertase (C4bC2a in the classical and lectin pathways, C3bBb in the alternative pathway). C3 convertases catalyze cleavage of C3 to products that lead to formation of C5 convertase (C4bC2aC3b in the classical and lectin pathways, C3bBbC3b in the alternative pathway) and eventually terminal complement activation, most commonly characterized by formation of the membrane attack complex (MAC, or C5b-9). Drug development has focused on a number of these steps (designated by red asterisks) in an attempt to refine regulation in certain pathologies. See the article text for more details.
MBL = mannose-binding lectin; MASP1 = mannan-binding lectin–associated serine protease 1; MASP2 = mannan-binding lectin–associated serine protease 2; C5aR = C5a receptor
All 3 pathways converge and culminate in production of C3 convertase, an enzyme that cleaves the propeptide C3 into immunologically active C3a (an anaphylatoxin with pro- and anti-inflammatory properties) and C3b products. C3b has numerous roles including opsonization of foreign pathogens and native cells (ie, tagging them for destruction by phagocytes), priming the adaptive system, and generating additional complement. For instance, C3b binding to C3 serves as substrate for further alternative-pathway generation of C3 convertase, while binding of C3b to C3 convertase generates C5 convertase.
Terminal complement activation results from C5 convertase cleaving C5 into C5a, a largely proinflammatory anaphylatoxin, and C5b. C5b binds C6 and C7 in the fluid phase before associating with the target membrane, then recruits C8 and triggers C9 polymerization in the plasma membrane. This forms the basis of the pore-forming membrane attack complex (MAC, or C5b-9) to facilitate osmotic lysis of cells and pathogens.
Complement activation is a feed-forward system in which activated proteins directly contribute to activation of subsequent components, rapidly amplifying the response. This is particularly evident in the alternative pathway, as it provides low-level activation of complement products, allowing the body to constantly and nonspecifically stand guard, in a process known as “tick-over.”6
Tick-over is believed to result from spontaneous hydrolysis of an internal thioester bond in C3, resulting in C3(H2O), which is recognized by circulating factor B, kicking off a series of protein interactions that result in the formation of an initial C3 convertase (C3[H2O]Bb, sometimes called C3b-like C3 or iC3) to generate fluid-phase C3b.7,8 As illustrated in Figure 2, C3b recognizes additional circulating native C3 and recruits factor B for formation of the major alternative pathway C3 convertase, C3bBb, leading to rapid upregulation of C3b products in an amplification loop.6
The alternative pathway drives amplification of complement activation. C3b generated from any activating pathway recognizes circulating native C3, recruiting factor B (B) and factor D (D) to form the major C3 convertase C3bBb. Properdin (P) stabilizes this convertase, enabling sustained amplification of C3b generation as C3 convertase (C3bBb) cleaves more C3. Factor H (FH) and factor I (FI) act as physiologic regulators of this process to control the amplification process. Various components of this system are current or future targets for therapeutic intervention (designated by red asterisks).
NORMALLY, COMPLEMENT IS A BALANCED SYSTEM
A complex system maintains the balance of complement activation and inhibition (Figure 2 and Table 14,5), with enough activation to protect against foreign threats but enough regulation to prevent collateral damage to the host from uncontrolled activation. In this system, negative regulators of complement in the serum (fluid phase) and attached to the cell membrane limit complement activation by decreasing the generation of anaphylatoxins, dissociating C3b from host cells, or inhibiting assembly of MAC.6
Key components of the complement system
Factor H is the main fluid-phase negative regulator of complement activation, working with factor I to prevent formation and limit the stability of C3 convertase in the alternative pathway (Figure 2),6 while C4b-binding protein inhibits C3 convertase formation in the classical and lectin pathways.
In addition to these soluble regulators, several membrane-bound proteins protect host cells from complement-mediated injury. Decay-accelerating factor (CD55) destabilizes both C3 and C5 convertases on cell surfaces, while membrane cofactor protein (CD46) serves as a critical cofactor for factor I–mediated cleavage of C3b and C4b on host cells. Defects in these membrane regulators result in severe complement-mediated disease, exemplified by CD55 deficiency (CHAPLE syndrome, characterized by complement hyperactivation, angiopathic thrombosis, protein-losing enteropathy, and systemic inflammation).9
COMPLEMENT DYSREGULATION IN MANY DISEASES
The balance between complement activation and inhibition is critical, as unregulated activation can damage host tissues, manifesting as a variety of diseases.
C3 glomerulopathies (C3 glomerulonephritis and dense deposit disease) are ultrarare but prototypic renal diseases in which complement dysregulation drives pathology.10,11 Paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy, also known as atypical hemolytic uremic syndrome, are 2 hematologic (and sometimes renal-limited) diseases where complement dysregulation is clearly pathogenic.12–15 In complement-mediated thrombotic microangiopathy, around 60% of patients have underlying pathogenic genetic variants in complement and complement regulator proteins.16
Aside from these prototypic complement-mediated diseases, complement activation plays an important role in the pathophysiology of a multitude of other diseases, including IgA nephropathy, antineutrophil cytoplasmic antibody–associated vasculitis, age-related macular degeneration, myasthenia gravis, and neuromyelitis optica.17–21 Management of these diseases has evolved over the past few years to include complement blockade at various levels.22 Complement activation is also thought to play a role in many other conditions, including membranous nephropathy, lupus nephritis, idiopathic membranoproliferative glomerulonephritis, and antiphospholipid syndrome.23
Insights gained from studying complement involvement and inhibition in kidney diseases are increasingly relevant not just to hematology but to many other disciplines, highlighting complement as a shared pathogenic axis across specialties, and a very promising therapeutic target.
COMPLEMENT INHIBITION AS TREATMENT
Given complement’s involvement in the pathogenesis of an expanding list of diseases, complement inhibition has emerged as a therapeutic strategy.24,25
Blocking C3 and C5 was the most obvious avenue to pursue, given that all 3 complement pathways converge on C3 and then C5. Eculizumab, a humanized monoclonal antibody against C5, was the first complement inhibitor to be approved; it was approved for paroxysmal nocturnal hemoglobinuria in 2007 and then for atypical hemolytic uremic syndrome in 2011.26 This paved the way for drugs targeting not only these downstream components (C3, C5) but also specific upstream components in the classical, alternative, and lectin pathways (factor B, factor D, mannan-binding lectin–associated serine protease [MASP] 2, C1s, C2). The soluble complement inhibitors factor H and factor I are also being used to attenuate complement activation.27
Some complement inhibitors are already approved for a variety of indications (Table 2), and many more are in advanced clinical trials. In addition, the science of complement blockade is evolving rapidly, with fusion proteins, products that silence RNA, and gene editing all on the horizon.27
Currently approved complement inhibitors
WHY THE EXCITEMENT ABOUT COMPLEMENT INHIBITORS?
Better outcomes
Complement inhibitors have revolutionized the treatment of many diseases that used to be plagued with very poor outcomes. The courses of diseases like paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are now significantly modified with C5 blockers, which achieve impressive response rates that were once unthinkable.26,27 This led to these agents being used off-label, with variable success, in many other diseases including C3 glomerulopathy, antibody-mediated rejection, and hematopoietic stem cell–associated thrombotic microangiopathy.
But blocking C5 has not worked in all these diseases, likely in part because of the many ways complement affects the immune system. For example, a C5 inhibitor was ineffective in treating C3 glomerulopathy, while drugs that block the complement system further upstream (eg, at C3) showed much more success. Pegcetacoplan (a C3 blocker) and iptacopan (which inhibits factor B) are FDA approved for managing C3 glomerulopathy, with pegcetacoplan also revolutionizing the care of patients with geographic atrophy secondary to age-related macular degeneration.
Less steroid use
Another major advantage of complement inhibitors is their steroid-sparing effect. Corticosteroids, while effective in many inflammatory conditions, have well-documented and significant side effects such as weight gain, hyperglycemia, osteoporosis, hypertension, and risk of infection. But now, patients with antineutrophil cytoplasmic antibody–associated vasculitis can get off steroids quicker if they receive avacopan, a C5a receptor inhibitor, without compromising response rates.28 Patients with IgA nephropathy now have effective non-steroidal, FDA-approved options with iptacopan and other agents.9 This steroid-sparing effect is a huge win for our patients who have long suffered the long-term consequences of chronic and repeated steroid therapy.
In nephrology, many phase 2 and 3 trials are currently evaluating the efficacy of complement blockade in various diseases including membranous nephropathy, lupus nephritis, idiopathic membranoproliferative glomerulonephritis, diabetic kidney disease, and focal segmental glomerulosclerosis.29 Excitingly, as complement plays a role in renal ischemia-reperfusion injury, complement inhibitors are also being studied to prevent delayed graft function after kidney transplantation and acute kidney injury following cardiac surgery.
Continued research is likely to expand the applications of complement inhibitors, making this class of medications a cornerstone in the management of many inflammatory disorders, and potentially more that have traditionally been considered noninflammatory, such as diabetic kidney disease and delayed graft function.
RISK OF MENINGOCOCCAL INFECTIONS
Infections are the major concern for patients on complement therapy. Most of the recommendations regarding infections are derived from studies of the C5 monoclonal antibodies eculizumab and ravulizumab, which have undergone longer postmarket surveillance and testing in more patient populations.
The greatest concern with these terminal complement inhibitors is a risk of infections by encapsulated bacteria, especially life-threatening meningitis from Neisseria species. Although the absolute numbers are low (2–3 cases per 1,000 patient years), patients on these drugs have 1,000 to 2,000 times greater risk of meningococcal infections than the general population.30 This risk remains high even with appropriate vaccination and antibiotic prophylaxis (Table 3).31
Vaccination guidelines for patients on complement inhibitors
Vaccination against encapsulated bacteria, supported by recommendations from the US Centers for Disease Control and Prevention, should be given 2 weeks before starting complement inhibitors. Importantly, meningococcal vaccination against all meningococcal serotypes (A, C, W, Y, and B) is required.31
If a complement inhibitor needs to be started earlier than 2 weeks after vaccination, antibiotic prophylaxis with amoxicillin (or ciprofloxacin or a macrolide if the patient is allergic to penicillin) is required. How long to keep giving prophylactic antibiotics is not clear, but they are generally continued for at least 2 weeks after starting the vaccination series, and some experts recommend continuing them until the meningitis vaccinations are completed (6 months) or even for as long as the patient receives a complement inhibitor.31
Importantly, the FDA requires that clinicians and patients enroll in a risk evaluation and mitigation strategy program to help lower the risk of these serious infections. Given the complexity of vaccination schedules, antimicrobial prophylaxis, and evolving pathogen risks, multidisciplinary collaboration—including infectious disease expertise—is often beneficial when starting or monitoring complement inhibitor therapy.
Avacopan, a C5a receptor inhibitor, does not increase the risk of meningococcal infections, as it targets only C5a, the anaphylatoxin byproduct of C5 cleavages, leaving C5b intact to eventually form MAC. A major area of uncertainty is whether the infectious risk seen with older terminal complement inhibitors will be seen with pathway-specific complement blockers (factor B, factor D, MASP 2) or proximal complement blockers, such as C3 inhibitors. While no current evidence supports an increased risk of meningitis with non-C5 complement inhibitors, all patients in these clinical trials still received appropriate vaccination, given the theoretical risks.
We support current US Centers for Disease Control and Prevention guidance that all complement inhibitors be presumed to have similar infectious risks,31 until longer-term data become available, considering the devastating consequences of infection and relative ease of reducing risk. Both patients and clinicians should be aware of these risks and the need for prompt evaluation and antibiotic therapy if such an infection is suspected. This not only includes the prescribing nephrologist, hematologist, or neurologist, but also the acute care clinicians at express clinics and emergency physicians, hospitalists, and intensivists.
Aside from the infectious concerns, these medications are reasonably well tolerated. Injection-site reactions are the most common side effects with injectable formulations, usually consisting of mild hypersensitivity (pruritus, headache, nausea, dizziness), but they can rarely be associated with anaphylaxis. Patients must be monitored for at least 1 hour after drug administration.
Metabolic disturbances, including hypertension, hyperlipidemia, and hypokalemia, have been noted in clinical trials, as have adverse hepatic events. Table 4 details medication-specific considerations.
Noninfectious medication-specific considerations and adverse effects with complement inhibitors
ARE COMPLEMENT INHIBITORS SAFE IN PREGNANCY?
Complement has been implicated in a variety of pathologic states in pregnancy. Complement-mediated thrombotic microangiopathy can be triggered in the peripartum period and is usually associated with other obstetric complications such as preeclampsia.32 Interestingly, a 2025 study reported that variants in the terminal complement pathway genes C5 and C6 were associated with and may predispose to preeclampsia.33
Eculizumab, the complement inhibitor best studied in pregnancy, is a category C drug, as it can cross the placenta and reach low levels in neonates, but it has been used safely in pregnancy-associated complement-mediated thrombotic microangiopathy.34
Similarly, eculizumab does not seem to be excreted in breast milk and is likely to be safe with lactation. Data on safety during pregnancy and lactation are lacking for other terminal and proximal complement inhibitors. More formal recommendations are expected in the future as data accumulate regarding safety of these drugs in these at-risk populations.
EXPENSIVE BUT WORTH IT?
Like other novel therapies, complement inhibitors are expensive, which becomes more relevant as many patients require extended therapy—sometimes lifelong! Even eculizumab biosimilars, soon to be on the market, are expected to have a high price tag. Cost-effectiveness analyses will be instrumental in the eventual accessibility and wider uptake of these effective therapeutic options.
Active areas of investigation include the optimal duration of complement inhibition and biomarkers to aid in monitoring recurrence of disease or therapeutic levels while on these medications.
COMPLEMENT: A SYSTEM TO REMEMBER
The complement system plays a crucial role in immune function and is increasingly implicated in the pathogenesis of various diseases across disciplines. Complement blockade has emerged as a therapeutic approach, providing the only effective treatment for some diseases, and promising effective and safer options in others.
The list of available and approved medications is rapidly increasing, and we expect that most practitioners will soon begin encountering patients on them with problems that will require in-depth knowledge of these medications. Forgetting about complement is no longer an option in providing optimal patient care.
DISCLOSURES
Dr. Bassil has disclosed consulting for Mallinckrodt Inc. Dr. Cavanaugh has disclosed consulting for Cerium Pharmaceuticals, Novartis Pharmaceuticals, Otsuka Pharmaceuticals, Travere Therapeutics, and Vera Therapeutics and acting as an advisor or review panel participant for Cerium Pharmaceuticals. Dr. Nakhoul has disclosed consulting for Akebia Therapeutics, Inc., Amgen, Boehringer Ingelheim, Calliditas Therapeutics, GSK, and Otsuka Pharmaceuticals. Dr. Taliercio has disclosed acting as an advisor or review panel participant for Amgen, Apellis Pharmaceuticals, and Calliditas Therapeutics. Dr. Mehdi has disclosed acting as an advisor or review panel participant for Alexion, Calliditas Therapeutics, and Novartis and teaching and speaking for Apellis Pharmaceuticals and GSK. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2026 The Cleveland Clinic Foundation. All Rights Reserved.
REFERENCES
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- Article
- ABSTRACT
- OLD DISEASES, NEW THERAPEUTIC HORIZONS
- THREE PATHWAYS THAT CONVERGE ON C3 AND THEN C5
- NORMALLY, COMPLEMENT IS A BALANCED SYSTEM
- COMPLEMENT DYSREGULATION IN MANY DISEASES
- COMPLEMENT INHIBITION AS TREATMENT
- WHY THE EXCITEMENT ABOUT COMPLEMENT INHIBITORS?
- RISK OF MENINGOCOCCAL INFECTIONS
- ARE COMPLEMENT INHIBITORS SAFE IN PREGNANCY?
- EXPENSIVE BUT WORTH IT?
- COMPLEMENT: A SYSTEM TO REMEMBER
- DISCLOSURES
- REFERENCES
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