Without any further comment here is the model mentioned in the previous article ( which if you have not already seen can be read HERE ). Have a go at all the questions.
So where did you end up?
Either YESs or NOs or DONT KNOWs to all.
Or most likely a mix of each . It could be expected that for most people using the model will be an iterative process. It could end up being a matter of pros and cons but not don’t knows.
Whatever the conclusions you have come to so far this model does not give medical advice to you on whether to stop and not stop treatment. Global Action cannot give medical advice. All it can do is from a “patients” perception of risk help you think where you would stand if you had to decide here and now. Some clarification. It is your choice.
Is it something to try , or to not move from where you are , or you just simply don’t know yet.
The important medical decision is for you and your doctor/medical specialist to make together when that time comes, if ever.
All this model does is give you something to talk to your doctor/medical specialist about based on what other aHUS specialists have said is relevant to such talks. There are no decision-making models at present for doctors/medical specialists to follow. Many doctors/ medical specialists are asking for them. Doctors/Medical specialists are split on whether stopping treatment is possible, or treatment is for life. Both opinions are right but not for all patients.16
However, the model is not all there is because in the notes which follow below there is more information to consider about each question. Followed by references to the evidence sources used in developing the proposed model.
To reiterate, this model is only for those aHUS patients who have been diagnosed with the complement mediated TMA form of aHUS, with or without a known genetic mutation and for whom complement inhibitor treatment has worked and been tolerated. The model is for patients of any age or gender.
Question 1.
A safe protocol for stopping treatment is a way to do it to avoid any long term harm to the patient. Currently no approved protocol has been published. However, some researchers have devised and embedded safe discontinuation practices in their trials. 1,3,5,6
There are common features in those practices which include Genetic Screening, Haematological, Kidney Function and Complement Activity Status Measurement, Informed Shared Decision , Monitoring Programme (including patient training), and a Rapid Return to Treatment Pathway.4
It can take the form of hospital visits for tests with or without seeing a doctor/medical specialist and also some patient self-monitoring. The intervals between each visit and testing get longer as time passes. Hospital visits can start weekly progressing to two weekly and then monthly and three monthly for a year or more. Similarly, patients own monitoring , which usually takes the form of a urine test with a dipstick may start off daily then every other day, weekly and so on until only done occasionally when a patient might feel unwell.5 Patients also are educated on how to spot signs and symptoms of relapse.3
So, there are “ best” practices tested which can be followed. Or your doctor/ medical specialist can spell out their own version of how it will be done. If none is offered, then that may be a game changer at the outset. Risk management of doing no harm is essential in all that is done.
Question 2.
These days it is accepted practice that although having the result of genetic testing is not necessary to start treatment of aHUS, it is essential for disease management. Particularly when it comes to optimal duration of that treatment. If not done, it should be done and further progress on discontinuing treatment should be delayed until it is done. Researchers have shown that genetic variants are a key predictive risk factor. 1,2,3,4,5,6,7,8,9,10 Though some may say genetics need not be the main driving force in any decision 1, they do not say genetic testing should not be done. What is found prepares the medical specialist and patient for what may happen either way.
Question 3.
By now you should know that it is uncontrolled complement that leads to you having your form of aHUS. Your doctor/medical specialist must be sure of that because there are other forms of aHUS which need to be treated differently.3 For 60% or so of patients with your type of aHUS, a disease predisposing genetic mutation or significant variant is found in at least one of the components of their complement system. In 40% or so of aHUS patients no genetic mutations are found which could have explained their uncontrolled complement activity. In some of those with no genetic mutations in complement control components there are anti factor H antibodies which compromise Complement Factor H efficacy. Resolving the level of such antibodies before discontinuation would resolve those patients’ compromised CFH and they become no genetic variant but with another blood test for antibodies to be monitored.
Where genetic variants have been found they can be classified as pathogenic ( disease causing), likely pathogenic, of unknown significance, likely benign or benign. The latter two are thought not to be disease predisposing.1
Researchers have found in their studies that patients with no, or the benign types of variants, rarely relapse, but they can do. 1, 3 Why that might be the case for no identified genetic variant is not fully understood. It could have course be that they have a different version of aHUS.
If patients have the pathogenic / unknown significance variants, research has found that it is more likely that a patient might relapse, but not always. 1,3,5 Genetics is the key risk factor. More thought is needed before going into stopping treatment when you have those variants because it is still possible to go into remission, if only for a reasonable period of respite from treatment.
By now several hundreds of aHUS patients have discontinued complement inhibitor treatment but not all outcomes have been reported in articles. Of 227 aHUS patients who participated in Global Action study of the aHUS diagnosis process 22% reported they were in remission off treatment. 56% of patients reported they were on complement inhibitor treatment and without a kidney transplant. 21
One examination of many published articles on treatment discontinuation concluded that the overall chance of relapse was 28.9%.13 This says that on average 71 out of 100 patients have gone into remission at the time of last follow up.
The average relapse rate findings within individual studies differ but seem to fall with the range of 20% to 32%1,2.3,5,6.7 However, within the overall averages different pathogenic variants have been found to have different likelihoods of causing a relapse. For example, for those with a disease predisposing CFH mutation, some may have a variant in a part of their CFH which produces a 90% chance of relapse, but in another part it may only a 20% chance of relapse15. Hence the need to delve further into things like “exons” and “splice regions” etc. It needs to be about you in very specific microscopic detail.13
Question 4
All researchers see the importance of being in hematological remission after your last bout of aHUS. This means no signs of a current thrombotic microangiopathy, TMA. Measurement of the same “variables” in the blood which were found to be abnormal when you were first diagnosed with aHUS, now, with complement inhibition, should be in their normal ranges. Platelets, LDH, Haemoglobin and Haptoglobin are measures of TMA activity in the blood. To those may be added any presence of any existing overactive complement. For example, evidence of SC5b-9 , which does the damage in aHUS, might mean that your complement system is active. Currently experts are not convinced that any presence of SC5b-9 is predictive of aHUS activity. Particularly when patients are still be being treated with a complement inhibitor. Other predictive measure are in the pipeline which may be of special importance in the predictive value of having no genetic mutations .17
Researchers are divided on whether you are ready for such hematological testing for discontinuing at 3 months1 or 6 months 3 after starting complement inhibition. This may be academic as you may have already been treated for a lot longer than that. Maybe more important for the “newbies” and how urgent they may want to try to discontinue. Researchers would not rule out the possibility of a relapse if you are in hematological remission when you start discontinuation of treatment, but they have rarely seen it.
Question 5
Previously relapsing before you were put on eculizumab is seen as a predictor of future relapse and the more it has happened before, the more likely it could happen again. If it has not happened to you, but to a member of your family with same genetic variant, that could be taken as a proxy for what could happen to you. Researchers are not saying that it is 100% certain and more evidence is needed.
Question 6
As with all aHUS incidence it is not just a matter of a genetic predisposition but there needs to be a trigger and whether that can be known or unknown. Triggers can happen occasionally and unpredictably e.g., an infections like influenza ( most relapses are found to occur following an infection 4 ) or occasionally and predictably as would be the case of pregnancy or elected surgery. 1.3.5 Or triggers can be continuous as it is in the case of a transplant. Researchers regard discontinuation in aHUS transplant patient as something needing a different decision-making process when it comes to predicting relapse. Transplant patients are often excluded from discontinuation studies though more is now understood about prophylactic or rescue complement treatment around the transplant and possible relapse. 1
Question 7
As well as evidence of hematological remission before discontinuation, the level of kidney recovery after the prior episode aHUS is important. In a relapse there might be some level of kidney injury before treatment is reintroduced. The extent of injury differs from person to person and how quickly a relapse diagnosis is made.
Stages of kidney disease are categorised by the estimated glomerular filtration rate eGFR. 20 Stage 5 is defined as an eGFR below 15 and is regarded as kidney failure requiring dialysis. Stage 4 is 15 to 29 eGFR , Stage 3 is split between Stage 3A and 3B , 30-44 and 45 to 59 eGFR respectively. Stages 2 and Stage 1 are eGFRs above that and are referred to as early-stage kidney disease and normal respectively.
Some margin of residual function is needed to ensure that relapse harm does not lead to someone going into kidney failure or increase the level of chronic kidney disease. Anyone in Stage 4 is at risk of that happening particularly if the patient is at the lower end of Stage 4. Researchers have included patients with Stage 3 and 4 kidney disease in their studies. Some acute kidney function decline can amount to more than 15 eGFR points so those with Stage 4 kidney disease may not have enough of a safety margin. Stage 3 and above is less risky but more data is needed to establish an acceptable degree of short term acute kidney function decline before rescue. This model therefore assumes caution.
Whilst the focus is on the kidney organ there can be non-kidney impact too, particularly important for those who experienced severe injury in previous incidents of aHUS. Most research has found no noticeable harm done to discontinuing patients 1, but one study mentions that previous non-kidney injury may be a predictor of relapse. 9
Question 8
A rapid pathway back to treatment on relapse is a key part of the safety net for reassuring those trying to stop treatment. Within 24 hours of signs of relapse is considered the best practice for not doing any long-term harm.1 There could of course be some acute kidney failure while eculizumab begins its work. However, researchers have found that any reduction in kidney function usually returns to pre discontinuation levels. 1,3,5 Extending the return to treatment time for a small number of patients has been associated with chronic injury, even at 7 days.3 Delaying for two to three weeks and more than half of relapses would cause long term harm. If delayed by months outcomes would be serious.8 This is crucial. If any barriers to a swift return in 24 hours cannot be overcome, then anyone would understand why a patient might not try discontinuing treatment. Safety has got to be embedded in all treatment discontinuation processes.
Question 9
Those clinicians conducting prospective trials emphasised the importance of patients collaborating, complying ,and adhering with safety protocols set up for them to ensure rapid treatment re-initiation on any relapse for them to get the best of outcomes.1,3,6
Anyone thinking of stopping treatment needs to be clear and understand what their commitment will mean for them. It is important to remember that any compliance burden reduces over time. It is more intense in the period when a recurrence is most likely to happen i.e. up to a year, then will fall off until only occasional vigilance is needed e.g. when patient has an infection.4 If a patients thinks it would be too difficult for them to play their part, then they need to say so.
Every patient is different. Some work, study, or care. Some live near and some live far from a hospital where the discontinuation monitoring will done. Visits can take time and cost and will be similar or more frequent than current complement inhibitor treatments of 26, or 6 to 7 per times year. Add on routine clinics and occasional relapse rule out checks, it can take time and it will cost and disrupt work and schooling and other day to day commitments. Will it be for you?
So now there is something to use for an important point in any aHUS patient’s treatment. It is a proposed model because Global Action recognises that the science can change. We can expect more research on this in the next 10 years.17 Also there are people who have experienced a relapse after treatment discontinuation who can either see that the model would have ruled out discontinuation for them or possibly add possible another risk factor which happened in their case. There are those may be have had no safety net and suffered harm.
So let’s position it as a dialogue on discontinuation has begun.
The following literature was used in the design and development of the model
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