Treatment

General

Treatment depends on the type and extent of amyloidosis and the associated organ damage.

“Precursor-product” concept as a treatment principle
The “precursor-product” concept is central to the treatment. The idea here is that further growth of the amyloid deposits comes to a halt when there is no longer any supply of precursor proteins.

Thus, AA-type treatment aims to minimize the levels of the inflammatory protein Serum Amyloid A (SAA) by maximally treating the underlying inflammatory process.

In the AL type, treatment aims to destroy the malignant plasma cells responsible for the production of the free light chains that deposit in this type of amyloid.

ATTR amyloidosis is treated with medications that stabilize the protein transthyretin or reduce its production in the liver so that it can deposit less as amyloid. A recent development is medicines, patisiran and inotersen, which work according to the technique of switching off a certain gene that provides the template for that protein (gene-silencing). Since January 1, 2019, the drug patisiran, which works on this principle, has been available in the Netherlands for patients with hereditary ATTR amyloidosis and nerve deterioration at an early stage (stage I or II polyneuropathy). A registration procedure for the drug inotersen is currently underway in the Netherlands.

Organ supportive therapy

In addition to the treatment that focuses on the underlying disease process, it is of course also necessary to provide supportive treatment for the organ dysfunction caused by the deposition of the amyloid. This varies a lot, such as treatment of impaired pumping function of the heart (heart failure), but also treatment of severe protein loss via the kidneys (nephrotic syndrome) with salt restriction, careful use of diuretic medication and possible ACE inhibitors or NSAIDs. In orthostatic hypotension, erythropoietin can sometimes be useful in addition to fludrocortisone. Caution is advised with agents such as amitriptyline for neuropathic pain due to the potential adverse effects on heart rhythm and blood pressure. Good nutrition (often in consultation with a dietician) is necessary in the event of impaired absorption of food in the intestine and other gastrointestinal problems.

Treatment options

AA amyloidosis
The treatment of AA amyloidosis is aimed at reducing the level of the inflammatory protein Serum amyloid A (SAA) to as low as possible by maximally combating the underlying inflammatory process.

This can be done, for example, by the effective surgical or antibiotic treatment of an infection source, by chemotherapy in Hodgkin’s disease and by effective suppression of inflammation (and therefore the SAA levels in the blood) in autoimmune and auto-inflammatory diseases such as rheumatoid arthritis and Crohn’s disease or familial Mediterranean fever (FMF). The arrival of medicines called biologicals, that very specifically inhibit inflammatory processes, has led to AA amyloidosis being much less common in the Netherlands than before. Your treating doctor can discuss with you which medicine is most suitable for you.

AL amyloidosis
In the AL type, treatment aims to destroy the malignant plasma cells responsible for the production of the free light chain that deposits in the form of amyloid. The plasma cells are destroyed by chemotherapy, if possible followed by a transplant of the patient’s own stem cells. You can find more information about the treatment of AL amyloidosis on the website of our Hematology department .

Wild-type ATTR amyloidosis (ATTRwt)
Due to aging processes, the protein transthyretin can become unstable, fold incorrectly and then form amyloid. This acquired type of ATTR amyloidosis can be treated with drugs that stabilize the protein transthyretin, making it less likely to form amyloid. These drugs, diflunisal and tafamidis, cannot cure the disease, but do inhibit disease progression. Recent studies showed that the survival of patients treated with tafamidis was better than that of patients treated with a placebo (a pill without active ingredients). The condition and quality of life deteriorated less rapidly in patients treated with tafamidis. Tafamidis was especially effective in people who still had relatively few heart failure complaints (NYHA I-II). Based on these data, it is unlikely that end-stage heart failure (NYHA IV) patients will have any survival benefit from tafamidis treatment. A registration procedure for tafamidis for people with acquired, wild-type ATTR amyloidosis is currently underway in the Netherlands. Treatment with tafamidis is available in a study setting. Ask your practitioner about the current state of affairs.

Hereditary ATTR amyloidosis (ATTRv)
In hereditary ATTR amyloidosis, a mutation (error) in the transthyretin gene causes this protein to be unstable, misfold and form amyloid. In the case of hereditary ATTR amyloidosis, a worsening of disease can be inhibited with drugs that stabilize transthyretin. Tafamidis is registered in the Netherlands for people with early stage nerve damage (stage I polyneuropathy) as a result of hereditary ATTR amyloidosis.

Transthyretin is, among other things, produced in the liver cells. What the protein should look like is recorded in the TTR gene (the blueprint). For the production of transthyretin, the TTR gene (the blueprint) is read in the cell nucleus and converted into messenger RNA (mRNA). This is, as it were, a template. This mRNA is used to communicate in the cell which building blocks the protein transthyretin must consist of.

In people with hereditary ATTR amyloidosis, there is a mutation (error) in the gene for transthyretin, which produces abnormal mRNA and ultimately abnormal transthyretin.

The results of research into drugs that work according to the principle of gene silencing have recently been published. These drugs, patisiran and inotersen, enter the bloodstream after administration and are absorbed into the liver cells. In the liver cells, these drugs destroy the mRNA for transthyretin (the template). In this way, selectively, the production of transthyretin is drastically reduced, reducing the amount of transthyretin entering the bloodstream and thus reducing the amount of transthyretin that can misfold and deposit as amyloid.

The study found that these drugs stop the increase in nerve damage (polyneuropathy) in many cases and also have a beneficial effect on the amyloid in the walls of the heart. Whether these drugs also have an effect on the development of amyloid in the eye or in the brain is not yet known.

As of January 1, 2019, the drug patisiran is registered in the Netherlands for patients with stage I and II polyneuropathy. The drug should in principle be administered via the bloodstream every three weeks for life. You can ask your doctor for more information.

At the end of 2019, a study was started in the Expertise Center into the effectiveness and safety of a drug that also works according to the principle of ‘gene silencing’, but only needs to be administered subcutaneously once every three months. You can ask your doctor for more information about this study.

Local amyloidosis
In the local forms of amyloidosis, surgery or radiotherapy are the only options for influencing the process and, if possible, stopping it. The chances are that the amyloid will return after surgery. It is often necessary to repeat the surgical removal of the amyloid one or more times before the process appears to have halted. In rare cases, the local deposition of amyloid is part of a systemic amyloidosis (usually the AL type) or related to a local monoclonal plasma cell proliferation. In those cases, treatment naturally focuses on the causal process.

Monitoring

After the diagnosis has been made, there will be regular checks. We call this monitoring. These checks are important for several reasons, namely:

1. To detect (in carriers of a mutation) the onset of the disease in good time, and then make adjustments in the treatment/strategy.
2. To detect an increase in illness in good time, and to make adjustments in the treatment/strategy.
3. To be able to determine the effect of the treatment and, if necessary, to make adjustments to the treatment/strategy.
4. To be able to identify side effects of the treatment and make adjustments to the treatment/strategy if necessary.
5. To be able to identify and relieve/treat complaints or symptoms as a result of the disease as effectively as possible.
6. To inform patients about the latest developments in the field of (the treatment of) amyloidosis and possibilities to participate in research into new medicines.
7. To participate in scientific research into various aspects of amyloidosis in order to improve care for patients in the future.
8. The frequency of checks, the type of examination required, and which medical specialists are involved depend on the type and extent of amyloidosis and the associated organ damage. Checks take place at regular intervals in the amyloidosis expertise center and, if necessary, interim checks can be carried out in another hospital closer to home (one of the affiliated treatment centers).

Our primary goal with each individual patient is to understand both the severity and course of the disease and the long-term effect of treatment (also called personalized medicine).
As a basis (A), a plan that can apply to all patients with that type of amyloid, supplemented with specific checks that apply to that patient in particular, with their symptoms and organ involvement.
With specific checks (B) relevant for the stage of the disease and the effect of the treatment being initiated. Every year it is necessary to evaluate the state of affairs and, if necessary, the plan is adapted to the situation.

National Amyloidosis Register (NAR)
A national amyloidosis register is being developed in collaboration with other University Medical Centers in the Netherlands. The register covers all types of systemic and local forms of amyloidosis. The aim of this national register is to map the occurrence and course of the disease and the effect of treatment of the different types of amyloidosis. In addition, the register can be used to quickly identify patients who could participate in clinical studies. Our proposal is that data can be entered initially by the expertise center and affiliated treatment centers and that in the long term, in collaboration with Stichting Amyloïdose Nederland , patient data and especially PROMs (patient registered outcome measurements) can also be entered.