aHUS- when PEX is a success

Article No. 314

28 January 2020

One of the interests of the aHUS patient community is whether remission from treatment can continue and if it does what makes those who go into remission different to those who cannot? This has been expressed in the Global aHUS Patients Research Agenda.
As more and more patients attempt a safe withdrawal  from eculizumab treatment,  the popularity of the remission question grows. But for most aHUS patients around the world access to eculizumab is something they can only dream about. At best their only hope is for a remission after plasma therapy to get their complement back to a controlled tick over.
Some aHUS patients do go into remission after plasma therapy only, but very little is known about them, only just some anecdotal reports.
The key plasma therapy employed in the early stages of treatment involves the aHUS  patient’s blood plasma , which has the defective complement,  being replaced with new plasma which has effective complement control components. This is called plasma exchange or PEX .
The exchange process may have to repeated several times because the patient’s own  defective complement components can return in time and exacerbate  attempts by PEX to control complement. However after several attempts complement activity can return to normal and a state of remission begins.
For aHUS patients remission means just normal complement activity levels which are under control and platelet counts  that fall within normal levels. Once that happens thoughts arise about  how likely it is that a relapse occurs  if something once again triggers complement activity.
Studies of eculizumab withdrawal address that concern and guide doctors to consider whether  there is any further need for treatment continuing.
Little research has been done on whether PEX can bring about a lasting remission though there is anecdotal evidence that for some with aHUS it can work.
An article appeared last autumn about a study by investigators from the Korean TTP/aHUS Registry. The  aim of the study was to look at blood biomarkers which could be used to diagnose whether a patient has either TTP and aHUS. The two diseases share clinical features, though in time TTP shows more neurological impact whereas aHUS has more renal  damage. But there are overlaps making differentiation difficult to do. However it is important diagnosis is done as quickly as possible.
TTP is usually suspected when a blood component ADAMTS 13  is less than 10% of its normal level. This  deficiency  is important to the mechanism of the disease as insufficiency leads to uncontrolled thrombotic activity. It is not the case for aHUS patients where uncontrolled activation of the alternative pathway of complement is the disease driver.
The researchers at the Registry set out to determine whether any difference could be found in the complement products  in TTP/aHUS patients’ blood which could aid a quicker differential diagnosis for aHUS.
Furthermore as PEX was the only treatment available to Korean patients at the time of the study , the researchers also looked at whether those biomarkers could determine whether aHUS patients would respond with good clinical outcomes to  PEX treatment.
They created three study groups, 48 TTP patients , 50 aHUS patients and 40 healthy volunteers. The aHUS group were tested for complement genetic mutations but only 9 were found to have any.
The groups were similar in age , around a median of 50 years, but there was a higher proportion of females in the TTP group but markedly less in the aHUS cohort , particularly the subset with genetic mutations.The TTP group showed more neurological symptoms, but a significant proportion of aHUS patients did too.
As well as the usual blood measures the  complement products they measured were C3a, Bb, C4d, C5b-9, C5a and of course  ADAMTS 13.
From the usual blood measures the research group found that the TTP Cohort had markedly less platelets than the aHUS group, whereas the latter had much higher creatinine , a sign of renal injury.
Although in both TTP and aHUS patients there were higher complement products than in the healthy group , little difference was found between TTP and aHUS patients except for the fragment Bb. Complement was clearly activated in TTP as well as aHUS.
As expected ADAMS TS 13 levels were lower in TTP patients. None of the aHUS patients fell below the 10% level where TTP would be suspected.
The researchers however found something novel in the ADAMTS 13 results in half of the aHUS patients. aHUS patient’s levels were expected to be higher than  those with TTP ( <10%) and the median level was 77% of normal ; but it was evident that those aHUS patients with even higher approaching normal ADAMTS 13 levels were more responsive to PEX treatment , experienced fewer exacerbations  and were more likely to go into remission. They also had less disease mortality. An important finding for possible prognosis in the early stage of treatment.
PEX is the only effective treatment  for TTP but when there is access to complement inhibitors PEX may only be used for the short term treatment of aHUS. This study suggest that some aHUS patients presenting with high ADAMTS 13 levels may respond more quickly and effectively before eculizumab needs to prescribed. Equally there could be a case that those with lower levels of ADAMTS 13 are less likely to benefit from PEX and should be converted to eculizumab as soon as possible.
One of the most noticeable aspects of the Korean aHUS cohort was how only a small minority of them were found to have susceptibility complement  genetic mutations , over 80 % of them were idiopathic with no evident cause of their TMA . This is the opposite of what is usually found in western countries. The researchers wondered whether ethnicity played a part in this.
As there are fewer idiopathic aHUS in western countries does this contribute to the conclusion that  PEX treatment is less  beneficial to aHUS in those countries.
In eculizumab withdrawal research studies done to date those patients who are idiopathic are also emerging as at less of risk of relapse from remission after eculizumab treatment is stopped.
It may be a leap even further but could also those with a higher  ADAMTS 13  levels in the early stages of aHUS  onset be predicted to respond more favourably to eculizumab withdrawal ?

The excellent article from the Korean TTP / aHUS Registry Group can be read in full by using this link HERE.



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