Monitoring of complement function in patients with aHUS can guide clinically appropriate dosing intervals without changing disease activity markers.24 The half-life of eculizumab is about 11 days, and dosing intervals may be safely extended beyond 2 weeks in select patients.25 The target minimum inhibitory serum eculizumab level necessary to inhibit complement-mediated hemolysis is 50 µg/mL and 35 mg/mL for aHUS and PNH, respectively. In a small pharmacokinetic pilot study, Gatault and colleagues noted that trough levels during eculizumab maintenance by enzyme-linked immunoabsorbent assay (ELISA) of 44 mg/mL to 59 mg/mL inhibited the complement cascade.26 We suggested that weight-based dosing aiming at a trough > 50 mg/mL (rather than fixed dosing at a fixed interval) would be a better maintenance strategy.
In select patients, a trial of gradual discontinuation by lengthening the dosing interval of eculizumab seems a reasonable and safe alternative to indefinite continuation of the drug. After a patient’s successful recovery, the initial and unknown trigger of aHUS may no longer play a role. Improvement in the patient’s medical condition may permit the restoration of the patient’s defenses to once again function normally. Eculizumab seemed to retain its efficacy in the small number of patients who relapsed. Those who relapsed had positive genetic markers.
Further arguments favoring trial discontinuation in patients without known genetic predisposition are that continuation is not without risk, particularly of meningococcal infection, necessity for infusion every 2 weeks for life, little is known regarding long-term risk of the drug, and a lot is known of its extreme cost. Suppression of C5 inhibitory effect can lead to increased susceptibility to infections, whereas increased C5 activity may lead to a continued autoimmune attack on native cells.
As proposed by others, we suggest that this decision be made on a case by case basis, tailoring treatment based on an individual’s genetics and medical history.27 Although the European Medicines Agency has approved lifelong therapy for aHUS, this may be appropriate only for patients who have aHUS complement mutations associated with poor outcomes.27 This approach may not be warranted, however, in a patient, such as the one presented with no genetic mutations, or in those with mutations of uncertain clinical consequence. In such cases, given that 90% of adults who have a relapse experience within the first year after an aHUS episode, a reasonable alternative may be a trial discontinuation.27,28 After 1 year of eculizumab therapy, a trial of discontinuation with urine dipstick monitoring for Hb (Hemastix) 3 times a week for relapse may avoid the unnecessary expense and risk for infection posed by lifelong therapy, and eculizumab may be effectively restarted in case of relapse.
We propose that in these cases it would be reasonable to perform a trial of discontinuation after 1 year of therapy with urine dipstick monitoring for relapse, as lifelong therapy may pose unnecessary expense and risk for infection. In fact, given the financial burden of prolonged therapy on society, we believe it is unethical to continue treatment in a patient with unknown risk for relapse without a trial of discontinuation, as evidence has shown good response to re-initiation of therapy in the event of relapse.28 Agencies that have negotiated or attempted to regulate the cost of eculizumab have been met with public media campaigns featuring afflicted children at risk of death without eculizumab. The public relations company behind these efforts received support from Alexion.29-31
Conclusion
Given the formidable cost and the international monopoly status of eculizumab for a life-threatening condition, prospective discontinuation trials supported by the manufacturer would seem warranted in select cases. Delineating which patients will have a chronic relapsing course and those who will not should be one of these clinical trials. For now, one can only wonder: What’s worse than having a rare disease like aHUS? Perhaps the cost of treatment for a potentially indefinite period of time—now that’s a “bitter pill.”32
