An Australian patient with catastrophic antiphospholipid syndrome that proved resistant to initial treatment was eventually responsive to eculizumab, per a recently-published case report.
The ‘instructive’ case involving the monoclonal antibody targeted against complement C5 highlights the importance of genetic testing as well as the central role of complement activation in the pathogenesis of catastrophic antiphospholipid syndrome (CAPS), according to the authors.
They described the case of a young woman with a history of previous lupus anticoagulant serology, who presented to a regional hospital with cardiogenic shock, a pulmonary embolus, oligoanuric renal failure and severe thrombocytopenia following upper respiratory tract failure.
Admitted to intensive care before transfer to St Vincent’s Hospital Melbourne, the patient deteriorated over the following week and a half, with worsening thrombocytopenia and ongoing hypocomplementaemia.
On days 7 and 8, she developed acute gastrointestinal bleeding with hypovolaemic shock, requiring two embolisations and blood product replacement (including platelets).
“There was concern that this represented a life-threatening deterioration for the patient and failure of initial treatment,” the team reported in BMJ Case Reports (link here).
It was about this time that the patient was diagnosed with probable primary CAPS in light of the multiorgan dysfunction, disseminated thrombosis, presence of aPL antibodies and normal ADAMTS13 activity, as well as the evolution of symptoms over a week.
Consequently, on day 11 of the presentation, weekly eculizumab 900 mg intravenous infusion was given for a total of four weekly doses. This accompanied relevant immunisations for encapsulated organism and antimicrobial prophylaxis.
The result was a “plateau of illness” following the first dose, with an improvement over the two weeks of the nadir platelet count and normalised complement enabling renal replacement therapy to be ceased.
The patient was then transitioned to high-dose prednisolone and oral hydroxychloroquine, ceased heparin, transitioned to enoxaparin and later changed to warfarin. They also completed six cycles of cyclophosphamide according to the Eurolupus protocol.
Recovery
Describing outcomes at nine months follow-up, the authors said there were no further episodes of thrombosis, while the patient’s renal and cardiac function had each recovered substantially.
On the other hand, MRI brain reported microinfarcts to bilateral supratentorial on high T2/fluid attenuated inversion recovery (FLAIR) signal attributed to her original presentation. And on repeat aPL antibodies, anticardiolipin remained positive as did lupus anticoagulant, while platelet count and complement levels had normalised.
Another important element of her care was genetic testing to assist discussions on future planning for renal transplantation and pregnancy, said the authors, who noted the patient’s history had included two spontaneous miscarriages.
Nevertheless, testing for exon genes associated with complement activation and regulations came up negative for variants of clinical significance, they said.
“Patients with CAPS harbour a high rate of germline variants in complement regulator genes; however, these are only found in 60% of cases,” the authors wrote.
“Observational studies have identified a similar rate of germline mutations in complement regulator genes to those with atypical haemolytic uraemic syndrome, which is conceptualised as the traditional complement-mediated thrombotic microangiopathy.”
“Although our patient had no detectable complement gene regulator mutation, there is still a potential for unknown variants yet to be discovered, and epigenetics is not accounted for in germline mutation testing.”
Eculizumab, a monoclonal antibody against C5, had been proposed as a targeted treatment for those patients with resistant CAPS due to the pathogenic association with complement activation, they added.
“Eculizumab has been successfully used in cases of recurrent or resistant CAPS, especially those where thrombotic microangiopathy (TMA) is prominent, with partial or complete response in 75% of patients,” the authors wrote.
“From case studies, eculizumab may have a key role for treatment when massive aPL-induced complement activation is present, particularly in the presence of thrombocytopenia.”
Another consideration was the impact of CAPS on future renal transplantation, the team noted.
“Limited evidence from case series prompts the hypothesis that eculizumab use in the peritransplant and post-transplant period may improve graft survival.”