Complement inhibition may be effective therapeutic strategy for antiphospholipid syndrome
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ORLANDO — Patients with catastrophic antiphospholipid syndrome appeared to have high rates of mutations in complement regulatory genes that could lead to uncontrolled complement activation and a more severe phenotype, according to study results presented during the plenary session of ASH Annual Meeting and Exposition.
The results also suggest complement activation has a pathophysiologic role in thrombosis associated with antiphospholipid syndrome.
A therapeutic strategy that includes complement inhibition should now be considered for patients with catastrophic antiphospholipid syndrome (CAPS) and refractory thrombotic antiphospholipid syndrome (APS), researchers noted.
“Antiphospholipid syndrome is defined as thrombosis, pregnancy morbidity or both along with persistently positive antiphospholipid antibodies,” Shruti Chaturvedi, MBBS, MS, assistant professor of medicine at Johns Hopkins University, said during the plenary session. “Long-term anticoagulation with warfarin is the standard of care for thrombotic antiphospholipid syndrome.”
Despite sufficient anticoagulation therapy, 10% to 30% of patients with APS experience recurrent thrombosis. CAPS is associated with a mortality rate of about 40% despite treatment.
The pathogenesis of APS complications is not fully understood. Recent animal studies suggested that complement activation is required for antiphospholipid antibody-associated thrombosis, and complement has emerged as a therapeutic target for refractory thrombotic APS and CAPS.
Chaturvedi and colleagues evaluated complement activation in the sera of patients with thrombotic APS by International Society on Thrombosis and Haemostatis criteria (n = 53), CAPS (n = 6) and systemic lupus erythematosus (n = 74).
Researchers evaluated complement activation using the modified Ham test, which is based on the principle that a paroxysmal nocturnal hemoglobinuria cell line that lacks the cell surface complement regulators CD55 and CD59 undergoes lysis in serum that contains activated complement.
Cell death served as a measure of complement activation, and cell surface deposition of complement product, including C3c and C5b-9, was detected by flow cytometry.
Researchers tested whether adding purified patient-derived antiphospholipid antibodies (anti-beta-2 glycoprotein immunoglobulin G [IgG]) to normal serum caused complement activation. They then performed targeted sequencing of 15 complement genes in study subjects, in addition to 22 patients with atypical hemolytic uremic syndrome and 36 healthy individuals who served as positive and negative controls.
Results showed an association of complement activation with thrombotic APS. A positive modified Ham assay, defined as cell killing of greater than 20%, was detected in 32.1% (n = 17) of patients with thrombotic APS and in all patients with CAPS compared with 6.8% (n = 5) of those with systemic lupus erythematosus (P < .001).
Most patients (79.3%) with a positive modified Ham assay had a history of thrombosis, compared with 38.4% of those with a negative modified Ham test.
Among patients with APS, modified Ham positivity appeared associated with triple positivity (lupus anticoagulant, anti-beta-2 glycoprotein-1 antibody and anti-cardiolipin antibody), which in turn appeared associated with higher risks for thrombosis (60%) than double (23%) or single (10%) positivity (P = .002).
Patients with APS also appeared more likely to demonstrate modified Ham positivity closer to a thrombotic event.
Additionally, results showed that antiphospholipid antibodies from patients activate complement in vitro. Anti-beta-2 glycoprotein IgG derived from four patients resulted in complement activation in the modified Ham assay. Flow cytometry confirmed cell surface deposition of complement activation products (C4d, C5b-9). This was inhibited when adding anti-C5 monoclonal antibodies or a factor D inhibitor.
Finally, results showed associations between CAPS and complement mutations. Rare germline mutations — defined as those with a minor allele frequency of less than 0.01 — in complement genes occurred in 62.5% (n = 5) of patients with CAPS, 22.6% (n = 12) of patients with thrombotic APS and 23.8% (n = 5) of patients with systemic lupus erythematosus compared with 50% (n = 11) of those with atypical hemolytic uremic syndrome and 19.4% (n = 7) of healthy individuals.
Mutation rates in CAPS appeared higher compared with rates in APS (P = .019), systemic lupus erythematosus and normal controls; rates appeared similar to those seen in atypical hemolytic uremic syndrome.
Rare variants found in CAPS included homozygous CFHR1-CFHR3 deletion, THBD P501L, CR1 S1982G plus homozygous CFHR1-CFHR3 deletion, CFHR4 R287H and CR1 V2125L.
“These results provide rationale for a clinical trial of complement inhibition to reduce mortality in severe antiphospholipid syndrome and catastrophic antiphospholipid syndrome,” Chaturvedi said. – by John DeRosier
Reference:
Chaturvedi S, et al. Abstract 4. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Chaturvedi reports advisory/consultant roles with Alexion and Sanofi and research funding from Shire/Takeda. Please see the abstract for all other authors’ relevant financial disclosures.