Complement: Deficiency Diseases

The complement system is crucial for defence against pathogens, removal of unwanted materials such as dying cells or immune complexes as well as for development of adaptive immune responses. Genetically determined deficiencies of components of the complement system are usually relatively rare but they result in many severe diseases such as an increased susceptibility to recurrent, severe infections, autoimmune disorders (systemic lupus erythematosus), glomerulonephritis including membranoproliferative glomerulonephritis type II, paroxysmal nocturnal haemoglobinuria or angioedema. Recently, mutations and polymorphisms in complement proteins, particularly complement inhibitors, have been associated with atypical haemolytic uremic syndrome and age‐related macular degeneration. The elucidation of the pathophysiological basis for the different clinical presentations of complement‐deficient individuals has contributed to a better understanding of the physiological role of complement in normal individuals as well as to the development of emerging therapies.Key ConceptsThe majority of complement deficiencies are rare but cause severe diseases.Deficiencies of the early components of the classical pathway (C1q/r/s, C4, C2) predispose to systemic lupus erythematosus.The majority of complement deficiencies predispose to infections either withNeisseriaspecies (deficiency of Factor D, Properdin, C5, C6, C7, C8, C9) or Gram‐positive bacteria (C1q/r/s, mannose‐binding lectin, C2, C4, C3, factor I).Mutations in C1q/r/s, C2, C4, C3 and factor I can cause glomerulonephritis.Paroxysmal nocturnal haemoglobinuria is caused by deficiency of complement inhibitors CD55 and CD59.Hereditary angioedema is found in patients with dysfunctional C1‐inhibitor.Atypical haemolytic uremic syndrome is mainly associated with mutations and polymorphisms in complement inhibitors.Age‐related macular degeneration is associated with polymorphisms in complement inhibitor factor H.

The complement system is a critical innate immune defense mechanism that also facilitates antigen recognition as well as antibody production through the adaptive immune response. Overall, complement activation contributes to the immune system's recognition and response to foreign pathogens and altered self. Regulating complement activation, particularly its powerful alternative pathway (AP) amplification loop, plays a key role in modulating tissue damage at sites of injury. Besides a predisposition to infections and autoimmunity (particularly systemic lupus erythematosus) in individuals deficient in activating components, variants in complement regulators are associated with multiple diseases including atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), and age-related macular degeneration (AMD). In particular, the pathogenesis of aHUS is commonly related to a rare heterozygous loss-of-function (LOF) mutation in the gene for complement factor H (CFH), CD46 [membrane cofactor protein (MCP)] or factor I (CFI) or a gain-of-function (GOF) secondary to a variant in factor B (CFB) or C3. The variants associated with complement regulators are the most prevalent and clearly demonstrate that cofactor activity (CA) is essential to control complement activation and thereby avoid collateral damage to normal tissues. Importantly, multiple studies have now established the therapeutic efficacy of blocking the membrane attack complex (MAC) with a humanized monoclonal antibody that targets the fifth component, C5. In this review, we primarily focus on insights derived from the assessment of rare variants in a membrane complement inhibitor CD46 in aHUS. We also discuss the putative pathological mechanisms relative to these variants of the complement system.

SARS-CoV-2 vaccination in patients with paroxysmal nocturnal hemoglobinuria: An Italian multicenter survey.

Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA-null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

Lessons learned from bone marrow failure in systemic lupus erythematosus: Case reports and review of the literature.

Comparative efficacy of complement inhibitors in complement Inhibitor–Naïve PNH: A network meta-analysis of randomized trials

Optimizing Complement Inhibitor Monitoring in PNH and Beyond

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients’ access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

The alternative pathway (AP) of the complement system plays a critical role in the pathogenesis of various human diseases, including age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and several glomerular diseases. Although the approved drug Iptacopan is available, it requires twice-daily oral dosing, resulting in suboptimal patient compliance. Using a scaffold-hopping strategy, we identified the clinical candidate (3R,4R)-15, which exhibits potent inhibitory activity against factor B (FB) and the AP, with IC50 values of 10.2 nM and 59.3 nM, respectively. Furthermore, this compound exhibits significantly improved pharmacokinetic properties, including an oral bioavailability of 69.2% in mice. Preliminary clinical studies indicate that (3R,4R)-15 has promising efficacy in patients with PNH. Its once-daily dosing regimen also offers the potential to markedly improve patient compliance. (3R,4R)-15 is currently in Phase 3 trials evaluating its efficacy for the treatment of PNH.

Advancements in complement inhibition for PNH and primary complement-mediated thrombotic microangiopathy.

We describe a 12-year-old girl with systemic lupus erythematosus (SLE) who first presented with an atypical hemolytic uremic syndrome (HUS) associated with hypocomplementemia, and compare the clinical manifestations and prognosis between SLE patients with HUS and thrombotic thrombocytopenic purpura in the reported literature. Diagnoses were based on renal failure, hemolytic anemia, and thrombocytonemia, including the observation of fragmented red blood cells, hypocomplementemia and on the American College of Rheumatology criteria for SLE. Cocktail therapy may have been effective against the pathological condition of SLE. In 4 patients with SLE and HUS, prednisolone and immunosuppressive drugs were administered, and none of the patients suffered from chronic renal insufficiency. The prognosis for SLE patients with HUS is good. These findings suggest that SLE should be suspected in any HUS patient presenting with hemolytic anemia, thrombocytopenia, acute renal failure and hypocomplementemia, and the therapeutic response and prognosis for SLE with HUS are good.

Emerging evidence suggests that activation of the complement system is critical in the pathogenesis of the novel coronavirus, SARS-CoV-2, the causative agent of COVID-19-related lung injury. Inhibition of the terminal complement pathway by targeting complement protein 5 (C5) may be an effective therapeutic intervention in CoV-mediated disease.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell (HSC) disease characterised by intravascular haemolysis, increased thromboembolic risk and bone marrow failure.2 The lack of GPI-linked complement regulators, especially CD55 and CD59, makes PNH erythrocytes exquisitely sensitive to complement activation, which can occur continuously, spontaneously and acutely and lead to devastating complications as a result of uncontrolled intravascular haemolysis. Precipitation of haemolysis, both in untreated patients and in those on anti-complement therapy,3 can be induced by any complement-activating events such as infection, trauma, surgery and pregnancy. Although viral infections have been shown to induce haemolysis by activating complement, there has been no published report of COVID-19 in the context of PNH during the ongoing pandemic, and neither has the added benefit of therapeutic complement inhibition, especially with monoclonal antibodies targeting C5 including eculizumab and ravulizumab, been examined. Here we report the clinical course, degree of intravascular haemolysis and outcomes of COVID-19 in four patients with PNH, two well-established on terminal complement inhibitor and two treatment-naïve PNH patients. Our index patient (patient 1, Table I) presented in mid-March 2020 with symptoms of fever (39·1°C), myalgia, dry cough and anosmia. She had a long-standing history of PNH and her disease activity, symptoms and haemolysis were well controlled on a long-acting C5 inhibitor, ravulizumab,4 and prior to this with a first generation monoclonal antibody, eculizumab.3 She was not hypoxic. SARS-CoV2 infection was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) assay. She did not have elevated inflammatory markers and her chest radiology was normal. Interestingly, her haemolytic markers were not significantly elevated, and terminal complement was adequately inhibited, as measured by an undetectable CH50/AH50. Yes Ravulizumab 3300 mg × 8 weekly 6 years Yes Eculizumab 1500 mg × 2 weekly 11 years Subsequently, we identified three additional PNH patients with concurrent presentation with clinical symptoms of COVID-19 and RT-PCR-confirmed COVID-19 (Table I). Two patients naïve to complement inhibitor treatment (patients 3 and 4), both with moderate/large PNH clones accompanied by a degree of haemolysis, required hospitalisation for COVID-19 pneumonia and also showed active signs of inflammation [high C-reactive protein (CRP)] and worsening haemolysis [high lactate dehydrogenase (LDH) compared to baseline], due to uncontrolled complement activation. The clinical course of these two individuals, not on anti-complement therapy but on primary prophylaxis with warfarin, was protracted and needed prolonged hospitalisation, readmission and supplemental oxygen therapy. Patient 2, on a high dose of eculizumab, had a similar presentation to the index patient and was found to be anaemic requiring blood transfusion, but with a clear chest radiograph, normal CRP and normal LDH. It is clear that complement plays a key role and is an integral component of the innate immune response to pathogens and its dysregulation or activation, either due to acquired deficiency of complement regulatory proteins (i.e. PNH) or due to viral infection (i.e. SARS-CoV-2), and can lead to significant tissue damage and importantly thrombosis due to endothelial damage.5 Our patients illustrate the presence of both conditions (PNH and COVID-19) concurrently and the differential response seen in patients already on effective complement inhibition compared to patients not on C5 inhibition. The beneficial effect of complement inhibition in not only controlling the intravascular haemolysis due to PNH, but also dampening the hyperinflammatory lung damage during COVID-19 has been illustrated with our small series. The adverse effect in patients not on C5 inhibitors may be circumstantial, as other known COVID-19 risk factors of mortality and morbidity,6 like older age, comorbidity, high body mass index (BMI) and male gender could have contributed to the worse outcome. SARS-CoV-2 infection,7 like other virus infections such as influenza virus and respiratory syncytial virus, is likely to induce massive complement activation in this ‘vulnerable’ group and can lead to severe life-threatening complications and hospitalisation. Emerging evidence suggests that the activation of the complement system, even in the absence of PNH, is key in the pathogenesis of COVID-19-related lung injury8 and therefore C5 inhibition may be an effective therapeutic strategy in CoV-mediated disease. Trials (SOLID-C19, CORIMUNO19-ECU and ALXN1210-COV-305), are ongoing to test the efficacy of terminal complement inhibition in dampening the progression of complications and improve outcomes in patients with COVID-19·9

Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing

Clinical Characteristics of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): A Retrospective Chart Review Study

Background and Aims aHUS is a rare, life-threatening, complement-mediated disease characterised by thrombotic microangiopathies. Established C5 inhibitors (C5is), such as eculizumab and ravulizumab, are effective for aHUS management but can be burdensome, typically requiring regular intravenous infusions every 2 weeks (eculizumab) or every 8 weeks (ravulizumab). Crovalimab is a novel C5i with low-volume, subcutaneous dosing every 4 weeks, with the possibility for self-administration. Crovalimab is currently being evaluated in two ongoing global, Phase III, single-arm trials in aHUS: COMMUTE-a (NCT04861259) and COMMUTE-p (NCT04958265). Crovalimab has also been evaluated in patients (pts) with PNH, another complement-mediated rare blood disorder, in the global, randomised, Phase III COMMODORE 2 (NCT04434092) and COMMODORE 1 (NCT04432584) trials (Röth AJH 2024; Scheinberg AJH 2024). Fatigue is a debilitating symptom that occurs in both aHUS and PNH. It is among the three most reported symptoms in aHUS (Greenbaum Kidney Int Rep 2020) and is the most common symptom in PNH (Cella J Patient Rep Outcomes 2023). Here, we report Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Smith PM R 2010) data, a widely used pt-reported outcome (PRO) measure in aHUS and PNH, with a median 2-y follow-up from COMMODORE 2 and 1. Method COMMODORE 2 enrolled C5i-naive pts and COMMODORE 1 enrolled C5i-experienced pts with PNH, respectively. Pts in COMMODORE 2 and 1 were randomised 2:1 and 1:1, respectively, to receive crovalimab (Arm A) or eculizumab (Arm B) during the primary treatment period (baseline to Week 25). After the primary treatment period, pts assigned to the crovalimab arm continued crovalimab (Arm A) and pts assigned to the eculizumab arm (Arm B) switched to crovalimab (Arm B switch) if continuing in the extension period (>Week 25). Fatigue was assessed at scheduled visits from baseline throughout the extension period to Week 97 using FACIT-Fatigue, a 13-item PRO instrument designed to assess fatigue-related symptoms and impacts on daily functioning, with a total score ranging from 0 to 52 (higher scores indicate less fatigue). A ≥5-point increase in FACIT-Fatigue score is considered a clinically meaningful improvement (Cella J Patient Rep Outcomes 2023), and the normative population mean score is 43.5–46.6 (Cella J Pain Symptom Manag 2002; Butt J Pain Symptom Manag 2010; Montan Value Health 2018). Mean FACIT-Fatigue scores are reported. The clinical cutoff date (CCOD) was 12 March 2024. Results In COMMODORE 2, 129 of the 135 pts randomised to crovalimab in Arm A continued crovalimab, and 68 of the 69 pts randomised to eculizumab in Arm B switched to crovalimab (Arm B switch), in the extension period. At the CCOD, 116 pts in Arm A and 59 pts in Arm B switch were receiving ongoing crovalimab treatment. At Week 25, Arm A pts had achieved fatigue levels similar to healthy people without PNH. Mean absolute FACIT-Fatigue scores were maintained from >Week 25 to Week 97 and ranged from 41.9–44.3 in Arm A and 40.3–42.2 in Arm B switch (Fig. 1). In COMMODORE 1, all 44 pts randomised to crovalimab in Arm A continued crovalimab and 40 of the 42 pts randomised to eculizumab in Arm B switched to crovalimab (Arm B switch), in the extension period. At the CCOD, 42 pts in Arm A and 32 pts in Arm B switch were receiving ongoing crovalimab treatment. Mean absolute FACIT-Fatigue scores remained stable from >Week 25 to Week 97 and ranged from 40.8–42.9 in Arm A and 38.2–40.8 in Arm B switch (Fig. 2). Conclusion In COMMODORE 2, the improvements in pt-reported fatigue levels observed with crovalimab in the primary treatment period were maintained over a 2-y median follow-up. Accordingly, in COMMODORE 1, fatigue levels remained stable over this same time frame. Overall, these results indicate the long-term benefit that can be achieved with crovalimab. The COMMUTE-a and COMMUTE-p trials evaluating crovalimab in aHUS are ongoing, including assessment of fatigue using the FACIT-Fatigue PRO measure, given its importance in this population.