“Atypical haemolytic uraemic syndrome (aHUS) is one disease where you really don’t want to wait until you see clinical signs until you act. By that stage there’s already end-organ damage and with that comes a whole raft of complexities,” notes Danny Hsu, Consultant Haematologist, Liverpool Hospital. The limbic spoke with Dr Hsu about how the management of aHUS has evolved, particularly his advice for clinicians who are likely to come across aHUS.

aHUS can pop up anywhere, the key is to always keep looking

“For years it wasn’t a disease you really wanted to proactively look for as the management was really a band-aid option. Plasma exchange (PE) or plasma infusion (PI) were the first-line treatment options which do not address the underlying cause.¹ Now that we have a way to target terminal complement as a clinician I feel like there’s more chances of staying ahead of the disease rather than constantly running behind,” noted Dr Hsu.

An extremely rare disease, aHUS is primarily a life-threatening disease caused by uncontrolled complement activation.² A consequence of prolonged complement activation is endothelial injury and platelet activation which manifests as thrombotic microangiopathy (TMA) leading to ischaemia and eventually end-organ damage.² Dr Hsu explained, “Historically aHUS was picked up in the emergency department following an acute TMA. I can recall several cases where we would give them PE and see their haematological parameters get better, but their cardiac, liver or renal function didn’t always improve as we’d hoped. What was frustrating back then was to give them all we had (PE) yet see the damage continue because complement was slipping through. It’s such an invasive way of treating with a sub-optimal outcome.”

Dr Hsu described how experience and protocols have changed the way aHUS is picked up in his department. “Often aHUS is picked up when people have an acute event. But don’t forget that it can be a sub-clinical, progressive disease.² Over the years our department has refined the screening protocol and we’re getting better at picking up changes in routine blood films. There are cases where now we work backwards – picking up changes in blood films before we see renal impairment. But even then it’s too late to prevent end-organ damage. That’s something that everyone needs to keep top of mind when it comes to treating early as well as considerations for how long to continue treating this relapsing disease.”³

The Australian consensus statement on the diagnosis and management of TMA acknowledges that diagnosis of TMA presents challenges, primarily due to the heterogeneity in its presentation.³ Symptoms of TMA can be general and non-specific, or extreme, which means TMA (and therefore aHUS) should be on the radar of a variety of healthcare professionals from general practitioners, haematologists, renal or other end-organ physicians and emergency department staff.³

Act early and use clinical judgement on treatment duration

Dr Hsu explained that eculizumab, a monoclonal antibody targeting the terminal complement protein C5 changed the way aHUS is treated. “Not only does it result in haematologic remission,⁴ we see improvements in end-organs such as the kidneys too if caught early.”⁴ An analysis of two prospective phase 2 trials showed that earlier, rather than delayed treatment (within 7 days of an event) was associated with a significantly greater improvement in eGFR, suggesting an improvement in clinical outcomes and even reversal of organ damage.⁴ Even in patients with long-standing renal disease, 4 out of 5 were able to cease dialysis during the trial and a majority of patients (88% in trial 1 and 100% in trial 2) discontinued PE or PI altogether.⁴

Dr Hsu noted that now it’s always a race to get patients on treatment as early as possible and is something his department is doing well. “Considering this is an extremely rare disease, our department has come leaps and bounds when it comes to identifying it. We’re doing well, with most patients starting treatment in 7 days and aside from 2 patients, everyone else has been able to come off dialysis. That’s a real achievement because I think a large benefit for patients is being able to come off dialysis. Not only from a quality of life perspective, but it means we’ve managed to halt or reverse some of the damage that’s been done.”

By far, the biggest debate and challenge Dr Hsu sees when it comes to aHUS is knowing how long to continue treatment. The Australian consensus statement does not address duration of treatment,³ and despite some clear guidance on when to use eculizumab for patients on dialysis and post-transplant patients, organisations like KDIGO do not provide guidance on individualised risk assessment for duration of therapy.⁵ Dr Hsu admits it’s a grey area which is currently left to clinical judgement. “We know we need to treat early, but how long for is really hard to tell and given it’s a rare disease probably hard to get clinical trial data on. The problem is that it’s not as simple as saying we’ll take patients off treatment and monitor blood films and put them back on treatment when we see changes. By then it’s already too late, even with sub-clinical disease. Once you see a change in the blood, there’s already end-organ damage occurring.”

An analysis of 93 patients enrolled in any of the five eculizumab trials who participated in a long-term follow-up study recently published showed the protective effect of treatment on risk of TMA and renal function may be compromised if treatment is discontinued.⁶  In patients who discontinued eculizumab, there were no TMA manifestations during on-treatment periods and a rate of 13.5 per 100 patient-years in off-treatment periods.⁶ That’s a 13.5-fold higher rate of TMA during off-treatment periods than on-treatment periods.⁶ Forty percent of patients who discontinued eculizumab has a decline in renal function, including those who re-initiated treatment.⁶

At the moment we’re left with trying to assess the risk in each patient, based on how many episodes they’ve had and the duration, their age of onset, presentation to the ED, even changes in creatinine and let that be our yard stick for deciding the risk of ceasing therapy. It’s not an ideal way to practice, but at the moment it’s the best we’ve got. Unfortunately relapse is still so unpredictable in this disease, but does occur.² So until we get a better handle on predicting relapse, if I had my way I’d keep patients on treatment as long as I can as the 10-year pharmacovigilance data looks good.”⁷

Identification of patients at risk for TMA while off treatment is something the Menne long-term study started to investigate. At this point in time more patients and a longer follow-up time is required to give power to subgroup analyses.⁶ However, a few trends were observed that suggest a higher risk of TMA off treatment in patients with:⁶

• complement genetic or auto-immune abnormalities
• paediatric onset
• history of multiple TMAs.

Safety of long-term eculizumab was also examined in the long-term follow-up study, where the median exposure was 45.9 months.⁶ Overall the treatment was reported as well tolerated, but bacterial infections (including meningococcal infections) were recorded.⁶ In all three confirmed cases the patients were vaccinated with an ACWY135 vaccine, but infection was caused by serotype B. “In the Menne study none of these infections resulted in the need to discontinue treatment,” explained Dr Hsu. “In the long-term pharmacovigilance paper, the authors also comment that immunosuppression may play a role in the infection rate, with some aHUS patients on dialysis or post-kidney transplant particularly vulnerable.”⁷

This article was sponsored by Alexion, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Alexion.

References:

1. Kaplan BS et al. Intractable Rare Dis Res 2014;3(2):34-45.
2. Macia M et al. Clin Kidney J 2017;10(3):310-319.
3. Fox LC et al. Intern Med J 2018;48(6):624-636.
4. Ariceta G. Pediatric Nephrol 2019;34(5):943-949.
5. Goodship TH et al. Kidney Int 2017;91(3):539-551.
6. Menne J et al. BMC Nephrol 2019;20:125.
7. Socie G et al. Br J Haematol 2019;185(2):297-310.