aHUS is a disorder of dysregulation of the alternative complement pathway in which there is uncontrolled activation of the alternative complement pathway resulting in inflammation, which produces endothelial injury, platelet activation and aggregation, leukocyte recruitment, and pro-coagulative signaling leading to thrombosis. Hence, it is called thrombotic microangiopathy, which is characterized by thrombocytopenia, hemolytic anemia, acute kidney injury, and other end-organ damage. Without treatment, it may progress to renal failure with mortality occurring in up to 7% of patients after one year.
Eculizumab (Soliris®, Alexion Pharmaceuticals, Boston, Massachusetts, United States), a complement component 5 targeted agent is a recognized therapeutic modality for PNH and is the only treatment agent approved by the FDA and European Medicines Agency as well as 49 countries worldwide for treating aHUS. Though eculizumab is very beneficial for the aforementioned diseases, it is associated with some major adverse effects. The prescribing information for the FDA-approved eculizumab includes a black box warning of the elevated risk of N. meningitidis infection. Since a membrane attack complex is required for the serum meningococcal bactericidal activity, its inhibition by eculizumab poses a risk of infection with meningococcus. Of note, the risk for invasive meningococcal infection increases by 1000-2000 times. The symptoms caused by N. meningitidis can range from fever, vomiting, headache, cold hands and feet, pallor or mottling of the skin to hemorrhagic rash, impaired consciousness, and death. The case fatality rate of meningococcemia is 40%. The incidence of N. meningitidis infection varies between 0.11 and 2.8 per 100,000 person-years in Europe, Australia, New Zealand, South America, and North America and 112 per 100,000 person-years in the African meningococcal belt zone. Meningococcal vaccination should be administered two weeks prior to initiation of eculizumab to prevent infection with meningococcus.
Author(s) Details:
Ravneet K. Dhanoa
Department of Internal Medicine/Hematology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Ramaneshwar Selvaraj
Department of Internal Medicine/Family Medicine/General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Shoukrie I. Shoukrie
Department of Orthopaedics/Traumatology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Anam Zahra
Department of Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Jyothirmai Malla
Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Tharun Yadhav Selvamani
Department of General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Sathish Venugopal
Department of Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Ranim K. Hamouda
Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Pousette Hamid
Department of Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
Recent Global Research Developments in Eculizumab Use in aHUS Treatment
Eculizumab Discontinuation in aHUS:
A prospective phase 4, multicentric, noncontrolled study [1] demonstrated that discontinuing Eculizumab is generally safe for most patients with aHUS once they achieve complete remission.
The overall risk of relapse after discontinuation was less than 25%, but it could be as high as 50% in patients with rare variants in at least one complement gene.
The study suggests a potential algorithm for discontinuing Eculizumab in patients who achieve complete remission.
Background on aHUS:
aHUS, also known as complement-mediated hemolytic uremic syndrome (CM-HUS), is characterized by mechanical hemolysis, renal impairment, thrombocytopenia, and preserved ADAMTS13 function.
Kidneys are most vulnerable, but CM-HUS can affect multiple organs.
Rare germline variants in complement genes or autoantibodies against complement regulatory proteins contribute to the disease.
Therapeutic terminal complement blockade with Eculizumab has significantly improved outcomes for aHUS patients.
Other Developments:
Ravulizumab, a long-acting C5 inhibitor, has also shown efficacy and safety in adult patients with aHUS [2] .
Optimal duration of Eculizumab therapy remains an area of ongoing research [3] .
References
- Brodsky, R. A. (2021). Eculizumab and aHUS: to stop or not. Blood, The Journal of the American Society of Hematology, 137(18), 2419-2420.
- Busutti, M., Maritati, F., Borelli, G. et al. Efficacy and safety of switching from Eculizumab to Ravulizumab for the maintenance of aHUS remission after kidney transplant: a preliminary experience. J Nephrol (2024). https://doi.org/10.1007/s40620-024-02005-7
- Menne, J., Delmas, Y., Fakhouri, F. et al. Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study. BMC Nephrol 20, 125 (2019). https://doi.org/10.1186/s12882-019-1314-1
