Amyloidosis-the Diagnosis and Treatment of an Underdiagnosed Disease
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MEDICINE
Review Article
Amyloidosis—the Diagnosis and Treatment of
an Underdiagnosed Disease
Sandra Ihne, Caroline Morbach, Claudia Sommer, Andreas Geier, Stefan Knop, Stefan Störk
T
he term systemic amyloidosis embraces a number of
Summary heterogeneous syndromes characterized by protein
deposits in the form of insoluble fibrils in the pa-
Background: Systemic amyloidosis is a multi-system disease caused by fibrillary tient’s tissues (1). The clinical findings vary according to
protein deposition with ensuing dysfunction of the affected organ systems. Its
the identity of the protein concerned and the extent and
diagnosis is often delayed because the manifestations of the disease are variable
pattern of organ involvement (1, 2). As yet there are no
and non-specific. Its main forms are light chain (AL) amyloidosis and transthyretin-
valid epidemiological data for systemic amyloidosis in
related ATTR amyloidosis, which, in turn, has both a sporadic subtype (wildtype,
Germany. Light chain (AL) amyloidosis is so far con-
ATTRwt) and a hereditary subtype (mutated, ATTRv).
sidered to be the most frequently occurring form (1, 3),
Methods: This review is based on pertinent publications that were retrieved by a with an incidence of 8.9–12.7/million person-years and
selective search in PubMed covering the years 2005 to 2019. prevalence of 40–58/million person-years (4). Hereditary
transthyretin (ATTRv) amyloidosis is estimated to affect
Results: No robust epidemiological figures are available for Germany to date. Both 5000–10 000 persons worldwide (5). These figures meet
AL amyloidosis and hereditary ATTR amyloidosis are rare diseases, but the prev- the definition of a rare disease. In contrast, age-related
alence of ATTRwt amyloidosis is markedly underestimated. The diagnostic algorithm wild-type transthyretin (ATTRwt) amyloidosis is being
is complex and generally requires histological confirmation of the diagnosis. Only diagnosed increasingly often: 25% of patients with heart
cardiac ATTR amyloidosis can be diagnosed non-invasively with bone scintigraphy
failure with preserved left ventricular ejection fraction
once a monoclonal gammopathy has been excluded. AL amyloidosis can be
(HFpEF) over 80 and 13% of those over 60 years of age
considered a complication of a plasma cell dyscrasia and treated with reference to
are thought to be affected (6, 7). This means that the
patterns applied in multiple myeloma. Despite the availability of causally directed
prevalence has been underestimated.
treatment, it has not yet been possible to reduce the mortality of advanced cardiac
This article reviews the data on systemic amyloido-
AL amyloidosis. Three drugs (tafamidis, patisiran, and inotersen) are now available
sis, focusing on the prognostic relevance of cardiac
to treat grade 1 or 2 polyneuropathy in ATTRv amyloidosis, and further agents are
involvement, on diagnosis of the disease, and on the
now being tested in clinical trials. It is expected that tafamidis will soon be approved
spectrum of emerging treatment concepts.
in Germany for the treatment of cardiac ATTR amyloidosis.
Conclusion: The diagnosis of amyloidosis is difficult because of its highly varied Methods
presentation. In case of clinical suspicion, a rapid, targeted diagnostic evaluation We carried out a selective search of PubMed for perti-
and subsequent initiation of treatment should be performed in a specialized center. nent records published in the period 2005–2019. The
When the new drugs to treat amyloidosis become commercially available, their use search terms were “systemic amyloidosis,” “AL amy-
and effects should be documented in nationwide registries. loidosis,” “ATTR amyloidosis,” “senile systemic amy-
loidosis,” “cardiac amyloidosis,” “familial amyloid
Cite this as:
polyneuropathy,” and “familial amyloid cardio-
Ihne S, Morbach C, Sommer C, Geier A, Knop S, Störk S:
myopathy.”
Amyloidosis—the diagnosis and treatment of an underdiagnosed disease.
Dtsch Arztebl Int 2020; 117: 159–66. DOI: 10.3238/arztebl.2020.0159
Pathophysiology
Systemic amyloidosis arises from the formation of in-
soluble amyloid fibrils, which in turn results from de-
Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital Würzburg, Germany: position of misfolded proteins. Over 30 proteins are
Dr. med. Sandra Ihne, Dr. med. Caroline Morbach, Prof. Dr. med. Claudia Sommer, known to be involved (8), causing different subtypes
Prof. Dr. med. Andreas Geier, Prof. Dr. med. Stefan Knop, Prof. Dr. med. Stefan Störk, PhD that cannot be distinguished by clinical means.
Medical Clinic and Policlinic II, Dept. of Hemtatology, University Hospital Würzburg, Germany: Dr. ● AL amyloidosis: This results from the deposition
med. Sandra Ihne, Prof. Dr. med. Stefan Knop
of monoclonal free light chains—systemically due to
Comprehensive Heart Failure Center Würzburg, University and University Hospital Würzburg, Ger-
many: Dr. med. Sandra Ihne, Dr. med. Caroline Morbach, Prof. Dr. med. Stefan Störk, PhD monoclonal gammopathy, multiple myeloma, or, more
Medical Clinic and Policlinic I, Dept. of Cardiology, University Hospital Würzburg, Germany:
rarely, B-cell lymphoma, or locally due to local produc-
Dr. med. Caroline Morbach, Prof. Dr. med. Stefan Störk, PhD tion of light chains. In systemic manifestations, circu-
Department of Neurology, University Hospital Würzburg, Germany: Prof. Dr. med. Claudia Sommer lating light chains have a direct cardiotoxic action (1).
Medical Clinic and Policlinic II, Dept. of Hepatology, University Hospital Würzburg, Germany: Deposits of light chains lead to mechanical interference
Prof. Dr. med. Andreas Geier and have cytotoxic and proapoptotic effects (1).
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 159MEDICINE
TABLE
The clinical manifestations of systemic amyloidosis
Organ Symptoms
Heart Dyspnea, peripheral edema, anasarca, pleural effusion, pericardial effusion, palpitations, irregular heart-
beat, syncopes, hypotension or regression of arterial hypertension, reduced heart rate variability
Kidney Edema, foamy urine, proteinuria (to the point of nephrotic syndrome) with predominant albuminuria, renal
failure
Liver Hepatomegaly, elevated liver stiffness, ascites, alkaline phosphatase elevation
Gastrointestinal tract Dysphagia, loss of appetite, weight loss, nausea, postprandial fullness, meteorism, diarrhea, obstipation,
gastrointestinal bleeding
Peripheral and Polyneuropathy (progressive, symmetric, axonal/small fiber, overall very variable), vegetative dysregulation
autonomic nervous (orthostatic dysregulation), intestinal motility disorder, urinary retention disorder, erectile dysfunction
system
Eye Dry eye, vitreous body opacity, glaucoma, retinal angiopathy
Soft tissues and other Macroglossia, hoarseness, coagulation disorders, purpura/cutaneous hemorrhage, e.g., periorbital, carpal
manifestations tunnel syndrome, swollen joints, splenomegaly, myasthenia, fatigue, biceps tendon rupture, lumbar spinal
stenosis
The clinical manifestations of systemic amyloidosis are extremely variable. Cardiac involvement relevant to the prognosis is seen particularly in AL and ATTR
amyloidosis.
● ATTR amyloidosis: The causal protein is trans- The manifestations of AL amyloidosis are pri-
thyretin (TTR), the transport protein of thyroxine and marily cardiac (about 75–80%) and renal (about
retinol-binding protein/vitamin A (9). Although the 65%); less frequently, the soft tissues (15%), the liver
underlying mechanism has not been fully elicited (10), (15%), the nervous system (10%), and the gastro-
the essential feature seems to be mechanical/enzymatic intestinal tract (5%) are involved. Cardiac involve-
cleavage of fragments from the TTR tetramer by pro- ment worsens the prognosis (1). Typically, AL
teases. This leads to destabilization and misfolding of amyloidosis progresses rapidly and thus demands im-
the monomers with tissue deposition triggered by mediate diagnosis and treatment. Around 30% of pa-
C-terminal fragments (10). Furthermore, amyloido- tients diagnosed with advanced cardiac amyloidosis
genic TTR mutations facilitate the deposition process in die within one year, and so far the effective new treatment
ATTRv amyloidosis by increasing thermodynamic options have not decreased this early mortality (1). The
instability (11). Besides mutant TTR, the deposits in 4-year survival rate varies between 40% and 60% (1).
patients with ATTRv amyloidosis also contain wild- ATTRwt amyloidosis frequently presents with a
type TTR (12). Altogether, more than 120 causal cardiac phenotype in the form of slowly progressing
mutations have been identified, typically inherited in an HFpEF (15). There is often accompanying neurologi-
autosomal dominant fashion with variable penetrance. cal involvement, e.g., symmetric, extremely variable
Analogously, natural TTR is co-deposited in ATTRwt sensorimotor polyneuropathy, but purely neurological
amyloidosis (9). manifestations are rare (4%). ATTRwt amyloidosis is
known to be associated with carpal tunnel syndrome
Clinical findings and lumbar spinal stenosis. Men are predominantly
The clinical manifestations of amyloidosis vary widely affected. The median duration of survival after diag-
depending on the subtype and on the pattern and nosis is about 4 years (15).
severity of organ involvement (Table). Owing to low Depending on the mutation, the phenotype of
specificity, prodromes are frequently misinter- ATTRv amyloidosis is predominantly cardiac, neuro-
preted—typically as symptoms of a common illness. pathic, or mixed cardiac/neuropathic (16). Much
Diagnosis is often delayed: 20% of patients with AL more infrequently, the kidney, gastrointestinal tract,
amyloidosis are not correctly diagnosed until 2 years or eye, leptomeninges/meninges, or vascular system
longer after the first symptoms, and in 42% of those (amyloidangiopathy) are involved.
with cardiac ATTRwt amyloidosis the diagnostic pro-
cess takes more than 4 years (13, 14). Findings that Diagnosis
should serve as “red flags” for continued diagnostic ef- The diagnosis of amyloidosis is a multi-stage process
forts include nephrotic syndrome, HFpEF, rapidly that should take place without delay (10).
progressive polyneuropathy, unexplained hepato-
megaly or diarrhea, unexplained weight loss, and other- Histological confirmation of suspected amyloidosis
wise inexplicable elevation of cardiac biomarkers in Histological demonstration of amyloidosis is essential
plasma cell dyscrasia (3). for confirmation of the diagnosis. A suitable
160 Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66MEDICINE
FIGURE 1
Suspected cardiac amyloidosis based on clinical features or imaging morphology
Monoclonal gammopathy? (free light chains, serum and urine immunofixation)
Abdominal fat biopsy, if necessary salivary gland biopsy*1
Skeletal scintigraphy*2
Bone marrow aspiration incl. Congo red staining
grade 2–3 grade 0 –1
no persisting clinical according to
persisting clinical suspicion according to Perugini
suspicion Perugini
et al.
et al.
Amyloidosis TTR
Subtyping Organ biopsy Biopsy including subtyping,
unlikely*3 mutation analysis
if necessary mutation analysis
depending on subtype regarding rare hereditary forms
identified
of cardiac amyloidosis
Diagnosis AL, Amyloidosis Diagnosis Diagnosis Diagnosis Amyloidosis
ATTR*4, ... unlikely*5 ATTRv ATTRwt ATTR*4, ... unlikely
Characterization of organ involvement
Cardiac involvement: NT-proBNP, troponin, echocardiography, cardiac magnetic resonance tomography, long-term ECG
Renal involvement: Proteinuria (including albuminuria), estimated glomerular filtration rate
Hepatic involvement: Liver size, alkaline phosphatase
Neuronal involvement: Clinical symptoms, neuroelectrophysiological work-up, if necessary small-fiber investigations
Diagnostic algorithm. The first step is to establish whether or not monoclonal gammopathy is present. If monoclonal gammopathy is absent
and skeletal scintigraphy is positive (cardiac tracer uptake grade 2–3), cardiac ATTR amyloidosis is confirmed (19); TTR mutation analysis is
recommended. If scintigraphy is negative (grade 0–1), biopsy including amyloid subtyping should ensue, accompanied if indicated by genetic
analysis for rarer forms (19).
If monoclonal gammopathy is present, histology including subtyping is indispensable. Painstaking characterization of organ involvement is
essential before commencement of treatment. Green arrow: “if positive, proceed to;” red arrow: “if negative, proceed to.”
*1 The diagnostic sensitivity of abdominal fat biopsy is 84% for cardiac AL amyloidosis, 15% for ATTRwt amyloidosis, and 45% for ATTRv
amyloidosis (depending on the underlying TTR mutation); for salivary gland biopsy after negative abdominal fat biopsy, sensitivity is 58%,
specificity 100%, and negative predictive value 91%.
*2 Suitable tracers are 99mTc-DPD, 99mTc-PYP, and 99mTc-HMDP
*3 Definitive exclusion only possible by organ biopsy; NB: risk of false-negative biopsy
*4 ATTRv and ATTRwt amyloidosis are differentiated by means of TTR mutation analysis
*5 NB: Risk of false-negative biopsy
NT-proBNP, N-Terminal pro-hormone brain-natriuretic peptide; TTR, transthyretin
low-invasive procedure is aspiration of abdominal fat, Suitable tracers are 99mTc-DPD, 99mTc-PYP, and
99m
the sensitivity of which depends on the subtype of amy- Tc-HMDP (10). Cardiac involvement in ApoAI
loidosis concerned (84% for cardiac AL amyloidosis, and AA amyloidosis might result in positive scinti-
15% for cardiac ATTRwt amyloidosis, 45% for cardiac graphy as well (10).
ATTRv amyloidosis (17). If the result is negative, sali-
vary gland biopsy should follow (18). Direct organ Amyloid subtyping and mutation analysis
biopsy should be resorted to only if the diagnosis re- Amyloid subtyping from a tissue sample obtained by
mains uncertain or in the presence of a constellation biopsy is obligatory, particularly because the presence of
such as isolated cardiac involvement with coexisting a monoclonal gammopathy does not prove the existence
monoclonal gammopathy. of AL amyloidosis: in 20% of cases, ATTR amyloidosis
Cardiac ATTR amyloidosis in the absence of is accompanied by monoclonal gammopathy (19). The
monoclonal gammopathy (negative immunofixation subtyping can be achieved by means of mass spectro-
from serum and 24-h urine together with normal scopy, immunohistochemistry (NB: higher error rate), or
levels of free light chains) is the only subtype amen- immunoelectron microscopy in a special laboratory with
able to noninvasive diagnosis by means of skeletal suitably experienced personnel. Should a potentially
scintigraphy (sensitivity > 99%, specificity 86%) hereditary form of amyloidosis be demonstrated, the
(19). corresponding gene must be analyzed for mutations.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 161MEDICINE
FIGURE 2
Confirmed AL amyloidosis
“FRAGILE” “FIT” (transplantation candidate)
CRITERIA (only one needs to be fulfilled): CRITERIA (all must be fulfilled):
– Biological age >65–70 years, ECOG > 2, NYHA stage > II – Biological age ≤ 65–70 years, ECOG 0–2, NYHA stage I–II
– NT-proBNP >5000 ng/L – NT-proBNP 2 organs involved (heart, kidney, liver, nervous system) – ≤ 2 organs involved (heart, kidney, liver, nervous system)
– Severe factor-X deficiency – No severe factor-X deficiency
Plasma cell infiltration in Plasma cell infil-
BM ≥ 10% or tration in BMMEDICINE
Treatment FIGURE 3
AL amyloidosis
In principle, AL amyloidosis can be understood as a
Treatment response
complication of plasma cell dyscrasia. It is treated with
reference to treatment patterns applied to multiple mye-
loma, i.e. targeting rapid elimination of the amyloido-
genic, (cardio)toxic light chains. Hematological Organ-related
Patients can be risk-stratified into “fit” and “frag- – Free light chains (FLC) and their – Cardiac:
difference (dFLC), respectively NT-proBNP, troponin, NYHA
ile” on the basis of clearly defined parameters of stage, left ventricular ejection
suitability for high-dose chemotherapy (Figure 2). – Serum immunofixation
fraction, wall thickness
“Fit” patients (10–25%) should receive high-dose – lmmunofixation from
– Renal:
24-h urine
chemotherapy. Induction chemotherapy is necessary proteinuria, eGFR, creatinine
only if the initial plasma cell infiltration of bone mar- – Hepatic:
row is >10% or the CRAB criteria (hypercalcemia, alkaline phosphatase, liver size
renal insufficiency, anemia, bone lesions) are fulfil-
led. Usually, a single administration of high-dose
chemotherapy follows stem-cell mobilization with Assessment of treatment response in systemic AL amyloidosis
granulocyte colony-stimulating factor (GCSF) with- Two qualities of treatment response can be distinguished: hematological and organ response.
out chemotherapy beforehand. Particularly patients The hematological response is defined either by the reduction in light chains and by the de-
with known translocation t(11;14) profit from the crease in the difference between involved and non-involved free light chains (dFLC), respec-
high-dose chemotherapy concept/high-dose melpha- tively. The organ response is determined individually for each organ involved, because this is
lan, while a poorer response has been reported for highly relevant for the prognosis, and is judged primarily on the basis of laboratory findings
bortezomib-based protocols (20, 21). (39). A low initial dFLC (MEDICINE
FIGURE 4
Production TTR tetramer TTR monomer TTR monomer Amyloid fibrils
in the liver (natural configuration) (misfolded)
Liver transplantation TTR stabilization Breakdown/reabsorption
TTR silencers – AG-10 – Anti-SAP antibodies/CPHPC
– AKCEA-TTR-LRx – Diflunisal – Doxycycline/TUDCA
– lnotersen – Epigallocatechin gallate – Epigallocatechin gallate
– Patisiran – Tafamidis – PRX004
– Vutrisiran – Tolcapone
Treatment approaches for ATTR amyloidosis. Liver transplantation is decreasing in importance because of its invasiveness, the scarcity of
organs, and the danger of disease progression due to deposition of wild-type transthyretin onto existing deposits. Alternative treatments, on the
other hand, have been gaining in importance. TTR stabilizers inhibit dissociation of the transthyretin tetamer into monomers and dimers and
thus prevent their deposition as amyloid fibrils. To date, only the TTR stabilizer tafamidis is approved in Germany for use against ATTRv amyloi-
dosis with grade I neurological manifestations. Gene silencers such as inotersen and patisiran suppress the hepatic synthesis of transthyretin
through mRNA interference and are licensed in Germany for use in ATTRv patients with grade I and II polyneuropathy. All other substances are
currently in clinical testing. The approved substances are written in bold type.
amyloidosis with polyneuropathy grade I or II, while gression as measured by the mNIS + 7 (difference
no agents have yet been licensed for cardiac involve- −19.7 points; pMEDICINE
cardiac manifestations (NEURO-TTRansform
[NCT04136184] and CARDIO-TTRansform Key Messages
[NCT04136171], respectively) are currently recruit-
ing. ● Variability of the phenotype, the absence of specific early symptoms, and the per-
Stabilization of the transthyretin tetramer can be ceived lack of treatment options are responsible for the typical delay in the diag-
achieved particularly with tafamidis (30), diflunisal nosis of amyloidosis.
(31), AG-10 (32), and tolcapone (33). The only TTR ● Nephrotic syndrome, cardiac insufficiency with preserved ejection function (HFpEF),
stabilizer licensed for use in Germany is tafamidis unexplained elevation of cardiac biomarkers in plasma cell dyscrasia, rapidly pro-
for ATTRv patients with grade I polyneuropathy; ap- gressive polyneuropathy, unexplained hepatomegaly or diarrhea may indicate the
proval for cardiac ATTRv amyloidosis is expected in presence of amyloidosis.
2020. Tafamidis occupies the thyroxine binding site,
● Histological demonstration of amyloid, including subtyping, is indispensable for diag-
thus preventing TTR tetramer dissociation. It is given
nosis. The sole exception is scintigraphic detection of cardiac transthyretin (ATTR)
orally and its primary effect is to slow the progress of
amyloidosis in the absence of monoclonal gammopathy.
the disease (34, 35). Administration at an early stage
in the disease course is crucial. In the randomized, ● Early initiation of treatment improves the prognosis of both light-chain amyloidosis
double-blind, phase-III ATTR-ACT trial on patients and ATTR amyloidosis, provided a licensed therapeutic is available for the patient’s
with cardiac ATTR amyloidosis (ATTRwt and pattern of organ involvement.
ATTRv), tafamidis significantly decreased the over- ● Cooperation with specialized interdisciplinary centers is essential.
all mortality (hazard ratio 0.70; 95% confidence in-
terval [0.51; 0.96]) and the number of cardiovascu-
lar-related hospitalizations (0.48 vs. 0.70/year) (36).
The adverse effects were comparable with those in
the placebo group (36). Diflunisal was found to slow tafamidis, € 320 000 for inotersen, and € 360 000 for
the progression of neurological manifestations com- patisiran. In-label use in Germany is covered by
pared with placebo (increase of 25 points in NIS + 7 health insurance.
score; difference 16 points, p < 0.001). The data re-
garding the efficacy of diflunisal in ATTR cardiomyo- Wild-type ATTR amyloidosis
pathy come from a small Japanese study (n = 40, No substance is yet approved for the treatment of
ATTRv amyloidosis, 24 months’ observation) which ATTRwt amyloidosis. The efficacy of tafamidis against
showed signs of stabilization of cardiac wall thick- cardiac ATTRwt amyloidosis has been demonstrated
ness. (36). Licensing in Germany is anticipated, but until that
A pilot study of another new TTR stabilizer, time only off-label use is possible.
tolcapone, has recently shown TTR stabilization in
all participants (NCT02191826), but phase-III data Conflict of interest statement
Dr. Ihne’s research was supported by the Comprehensive Heart Failure
are lacking. Because tolcapone penetrates the Center (CHFC) Würzburg and the Interdisciplinary Center of Clinical
blood–brain barrier, its short-term TTR-stabilizing ef- Research (IZKF), Würzburg. She has received funding for a project of her
fects have been investigated in an early phase-I study own initiation from Akcea; consultancy and lecture fees from Takeda,
Pfizer, Janssen, and Akcea; and reimbursement of congress registration
in patients with symptomatic and asymptomatic fees as well as travel and accommodation costs from Takeda, Pfizer,
leptomeningeal involvement; however, the results Akcea, and Alnylam. An internship abroad was supported by ONLUS.
have not yet been published (NCT03591757). Dr. Morbach carries out her research in the framework of a cooperation
Doxycycline/tauroursodeoxycholic acid (TUDCA) agreement between Tomtec Imaging Systems and the University of
Würzburg, supported by the Bavarian Digital Master Plan II. Furthermore,
targets acceleration of fibril degeneration and fibril she is a member of the patient selection board of EBR Systems and has
resorption (37). The studies conducted to date have participated in the advisory boards of Akcea, Alnylam, and Pfizer. She has
received funds to support congress travel costs from Orion Pharma and
small case numbers and suggest a positive effect in Alnylam and lecture fees from Alnylam.
patients with cardiac involvement. A larger random- Prof. Sommer is a member of the advisory boards of Akcea, Alnylam, and
ized, placebo-controlled phase-III trial in patients Pfizer. She has received payments for the preparation of scientific meetings
with ATTRwt and ATTRv amyloidosis is now recruit- from Alnylam and Pfizer, and has received funding for a project of her own
initiation from Pfizer.
ing (NCT03481972). Other substances currently
Prof. Knop is a member of the advisory boards of Celgene, Amgen, Bristol-
being tested include the monoclonal antibody Myers Squibb, and Molecular Partners.
PRX004, directed against monomers and deposited Prof. Störk is supported by the CHFC Würzburg, and by the German
TTR amyloid (38). Federal Ministry of Education and Research (BMBF). He has received
The potential significance of the novel treatments consultancy and lecture fees as well as reimbursement of travel costs from
AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Servier.
is not yet clear—no studies comparing them directly
Prof. Geier is a member of the steering committees of Gilead, Intercept,
have been published. According to an expert recom- and Novartis. He receives consultancy fees from AbbVie, Alexion, BMS,
mendation, the primary use of gene silencers is Gilead, Intercept, Ipsen, Novartis, Pfizer, and Sequana, and has received
worthwhile particularly in aggressive disease. It is lecture fees from AbbVie, Alexion, BMS, CSL Behring, Falk, Gilead,
Intercept, Merz, Novartis, and Sequana.
important to perform genetic testing of potential car-
riers of mutations (eMethods) and to initiate treatment Manuscript received on 25 August 2019, revised version accepted on
12 December 2019
as soon as the first manifestations are noted. The
mean annual cost of treatment is around € 160 000 for Translated from the original German by David Roseveare
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 165MEDICINE
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abdominal fat aspiration in cardiac amyloidosis. Eur Heart J 2017; 38: 1905–8. amyloidosis and low free light-chain burden have distinct clinical features and
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diagnosis of systemic amyloidosis: results of a prospective study in 62 patients.
Amyloid 2011; 18 (Suppl 1): 80–2. Corresponding author
19. Gillmore JD, Maurer MS, Falk RH, et al.: Nonbiopsy diagnosis of cardiac trans- Prof. Dr. med. Stefan Störk, PhD
thyretin amyloidosis. Circulation 2016; 133: 2404–12. Interdisziplinäres Amyloidosezentrum Nordbayern,
Deutsches Zentrum für Herzinsuffizienz (DZHI), Universitätsklinikum Würzburg
20. Bochtler T, Hegenbart U, Kunz C, et al.: Translocation t(11;14) is associated with
Am Schwarzenberg 15, Haus A15
adverse outcome in patients with newly diagnosed AL amyloidosis when treated
with bortezomib-based regimens. J Clin Oncol 2015; 33: 1371–8. 97078 Würzburg, Germany
stoerk_s@ukw.de
21. Bochtler T, Hegenbart U, Kunz C, et al.: Prognostic impact of cytogenetic aberra-
tions in AL amyloidosis patients after high-dose melphalan: a long-term follow-up
study. Blood 2016; 128: 594–602. Cite this as
Ihne S, Morbach C, Sommer C, Geier A, Knop S, Störk S:
22. Bochtler T, Hegenbart U, Kunz C, et al.: Gain of chromosome 1q21 is an indepen- Amyloidosis—the diagnosis and treatment of an underdiagnosed disease.
dent adverse prognostic factor in light chain amyloidosis patients treated with Dtsch Arztebl Int 2020; 117: 159–66. DOI: 10.3238/arztebl.2020.0159
melphalan/dexamethasone. Amyloid 2014; 21: 9–17.
23. Sanchorawala V, Palladini G, Kukreti V, et al.: A phase 1/2 study of the oral protea- ►Supplementary material
some inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood 2017; 130:
597–605. For eReferences please refer to:
www.aerzteblatt-international.de/ref1020
24. Muchtar E, Dispenzieri A, Leung N, et al.: Depth of organ response in AL amyloi-
dosis is associated with improved survival: grading the organ response criteria. eMethods, eBox, eTable:
Leukemia 2018; 32: 2240–9. www.aerzteblatt-international.de/20m0159
166 Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66MEDICINE
Supplementary material to:
Amyloidosis—the Diagnosis and Treatment of an Underdiagnosed
Disease
by Sandra Ihne, Caroline Morbach, Claudia Sommer, Andreas Geier, Stefan Knop, and Stefan Störk
Dtsch Arztebl Int 2020; 117: 159–66. DOI: 10.3238/arztebl.2020.0159
eReferences
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eBOX
mRNA interference
Messenger RNA (mRNA) contains a transcript of a gene
segment. Normally it transports this information from the
cell nucleus to the ribosomes, so that, with the aid of the
transcript, the corresponding proteins can be formed.
mRNA interference occurs when short segments of
RNA (e.g., siRNA or oligonucleotides) interact with
autologous RNA and various protein complexes. This
destroys the mRNAs, preventing formation of the
corresponding proteins.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material IMEDICINE eMETHODS Presymptomatic genetic testing and follow-up of objective symptom or clinical correlate thereof that is persons with TTR mutations definitively associated with the onset of ATTR amy- A decisive role is played by early detection of develop- loidosis (sensorimotor neuropathy [changes relative to ing symptoms of amyloidosis in carriers of amyloido- baseline], autonomic neuropathy or neuronal/sexual genic mutations, because there are no preventive inter- dysfunction, cardiac involvement, renal or ocular in- ventions and the available treatments are most effective volvement) or a symptom that is probably associated in the early stages of the disease (e1). Presymptomatic with disease onset despite absence of identifiable genetic testing should be offered to the relatives of pa- clinical signs together with an abnormal test result or tients with ATTRv amyloidosis. Especially important in two abnormal test results without subjective symptoms. this regard is diagnostic investigation of siblings at the age where disease onset can be anticipated. Particular Supportive treatment care should be taken in deciding the timing of testing in Optimal fluid management with primary use of cases where a greater elapse of time before disease diuretics is vital, whereas conventional cardiac insuffi- onset seems likely. Factors such as negative impacts of ciency treatment in the absence of evidence is of knowledge of the mutation on quality of life and psy- secondary importance. Calcium-channel blockers are chological wellbeing should not be underestimated. contra-indicated owing to their negative inotropic ac- The German law on genetic diagnosis stipulates that tion and potential interaction with the amyloid fibrils advice should be provided by a human geneticist or a (e3, e4). physician with subject-linked permission for genetic In the presence of symptomatic bradycardia or counselling. marked chronotropic incompetence the use of a car- Following a recently issued international expert diac pacemaker may be worthwhile. Insertion of an recommendation, the first step is to define the ex- implantable cardioverter–defibrillator (ICD) can be pected time of disease onset, based on the exact nature considered in a patient with malignant cardiac ar- of the mutation and the onset of disease in the index rhythmia. However, it has not yet been shown that patient (e2). Monitoring should begin with an exhaus- prophylactic ICD implantation prolongs long-term tive basic work-up 10 years before this time, followed survival (e5). by annual visits. The schedule must be adjusted Symptomatic hypotension as a consequence of au- according to the anticipated aggressiveness of the dis- tonomic nervous system involvement may necessitate ease. Equally, the specific investigations performed the administration of midodrine and/or fludrocorti- depend on anticipated disease phenotype (e2). sone together with physical measures such as Fulfillment of minimal criteria for the diagnosis of compression treatment (e6). Motility-enhancing or ATTR amyloidosis in known carriers of TTR mu- -inhibiting drugs can be given to treat gastrointestinal tations should trigger initiation of treatment (e2): an symptoms. Adequate calorie intake is essential. II Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
eTABLE
Treatment approaches and selected study results in ATTR amyloidosis
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase II/III, 128 pat. (18–75 y) with Primary: Evaluation of tafamidis vs. placebo AEs with tafamidis similar Licensed in Germany
multicenter, early-stage neurological 1. Percentage of responders measured using NIS-LL – Intention-to-treat analysis: to placebo for pat. with grade I
double-blind, manifestation of ATTR at 18 months; response: improvement or stabilization (change by NIS-LL response rate 45.3% vs – Interruption of study polyneuropathy in
placebo-controlled, amyloidosis and positivityIV
MEDICINE
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase III, 441 pat. (18–90 y) with Primary: Evaluation of tafamidis pooled vs. Safety profile comparable Licensed in Germany
ATTR-ACT, Maurer et al. 2018 (NCT01994889) (36)
multicenter, cardiac manifestation of Combination of overall mortality and incidence of cardiovascular-re- placebo: between tafamidis and for pat. with grade I
double-blind, ATTRwt or ATTRv amyloi- lated hospitalization (baseline vs. 30 months) – Overall mortality (all-cause): 78 of placebo, previously polyneuropathy in
placebo-controlled, dosis (n = 106) 264 (29.5%) vs. 76 of 177 described increased fre- ATTRv amyloidosis;
2 : 1 : 2 randomi- – Tafamidis 20/80 mg: Secondary (baseline vs. 30 months): (42.9%); hazard ratio 0.70 [0.51; quency of diarrhea and so far only in Japan
zation (tafamidis n = 264 (n = 63 ATTRv, 1. Overall mortality 0.96] urogenital infections not and USA for ATTR-
80 mg/d vs. n = 201 ATTRwt) 2. Incidence of cardiovascular-related hospitalization – Frequency of cardiovascular hos- confirmed related cardio-
tafamidis 20 mg/d – Placebo: n = 177 3. Change in walking distance in 6-min walking test pitalization 0.48 vs. 0.70/year, myopathy; licensing
Tafamidis
vs. placebo) (n = 43 ATTRv, n = 134 4. Change in KCCQ overall score relative risk ratio 0.68; [0.56; 0.81] in Germany expected
ATTRwt) 5. Cardiovascular-related mortality – At 30 months, less deterioration in in 2020
– Observation period 6. Percentage of pat. with stabilized TTR at 1 month 6-min walking test: 75.7 m [stan-
30 months dard error ± 9.2; pDeutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase II, Cardiomyopathy in Primary: Good tolerance, almost complete Not licensed
Judge et al. 2019 (NCT03458130) (e13)
randomized, ATTRv/wt amyloidosis Safety and tolerance (AEs) stabilization
double-blind, – n = 49
placebo-controlled – Observation period Secondary:
(AG-10 vs. 28 days Pharmacokinetics and pharmacodynamics
placebo)
Phase III, Cardiomyopathy in Primary: Study currently recruiting To be reported Not licensed
randomized, ATTRv/wt amyloidosis Walking distance in 6-min walking test at 12 months
AG-10
double-blind, – 510 participants planned Overall mortality and frequency of cardiovascular-related hospitaliz-
placebo-controlled ation at 30 months
(AG-10 vs.
ATTRIBUTE-CM (NCT03860935)
placebo) Secondary:
1. Change in KCCQ overall sum scores at
12 months compared with baseline
2. Change in 6-min walking test at 30 months compared with baseline
3. Change in KCCQ overall sum scores at
30 months compared with baseline
4. Incidence of treatment-associated events (SAE, AEs) within 12
months
5. Incidence of treatment-associated events (SAE, AEs) within 30
months
6. Overall mortality at 30 months
7. Incidence of cardiovascular-related hospitalization within 30
months
8. Cardiovascular-related mortality at 30 months
9. Diverse pharmacodynamic parameters
Phase III, double- Pat. with neuronal Primary: Placebo vs. diflunisal Incidence of gastrointesti- Not licensed
blind, manifestation of biopsy- Difference in progression of polyneuropathy between treatments, – NIS + 7 score increase by 25.0 nal, renal, cardiac and
placebo-controlled, confirmed ATTRv documented by means of NIS+7 (baseline, at 1 and 2 y) [18. 4; 31.6] vs. 8.7 [3.3; 14.1] hematological AEs similar
Berk et al. 2013 (NCT00294671) (e7)
1:1 randomization amyloidosis (18–75 y) points, difference 16.3 [8.1; 24.5] to placebo; incidence of
(diflunisal – 130 pat. Secondary: points (pVI
MEDICINE
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase III, Pat. (18–85 y) with Primary: Evaluation of patisiran vs. placebo Overall incidence and type Licensed in Germany
APOLLO, Adams et al. (2018) NCT01969348) (27)
multicenter, neuronal manifestation of mNIS + 7 (baseline vs. 18 months): of AEs similar for patisiran for pat. with grade
double-blind, ATTRv amyloidosis – mNIS + 7 change −6.0 ± 1.7 vs. and placebo, but 20% mild I–II polyneuropathy in
placebo-controlled, n = 225, cardiac involve- Secondary (changes baseline vs. 18 months): 28.0 ± 2.6 (difference −34.0 to moderate infusion reac- ATTRv amyloidosis
2 : 1 randomization ment in n = 126 (56%) 1. Norfolk QoL-DN Questionnaire points; p < 0.001) tions in patisiran arm vs.
(patisiran 0.3 mg/ – Patisiran n = 148 2. Neurological Impairment Score–Weakness (NIS-W) – Change in Norfolk-QoL-DN: 10% in placebo arm
kg vs. placebo – Placebo n = 77 3. R-ODS score −6.7 ± 1.8 vs. 14.4 ± 2.7
every 3 weeks) – Observation period 18 4. 10-min walking test (difference −21.1 points; pDeutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase III, Pat. (18–82 y) with Primary: – Change in mNIS+7: −19.7 points Glomerulonephritis, Licensed in Germany
multicenter, neuronal manifestation of 1. Change in mNIS+7 composite score (baseline vs. week 66) [−26.4; −13.0]; (pVIII
MEDICINE
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Single-center study Pat. with ATTR-related Primary: – Decrease in LV mass of 6% on None reported Not licensed
cardiomyopathy Left-ventricular mass and ejection fraction cMRI (196 g [100; 247] vs. 180 g
(64–80 y) (measured on cMRI) [85; 237]; p = 0.03)
aus dem Siepen et al. 2015 (e9)
– n = 25 (only ATTRwt) – Decrease in total cholesterol of
– 600 mg EGCG for at 8.4% (191 [118; 267] vs. 173 [106;
least 12 months 287] mg/dL; p = 0.006)
– LVEF stable on cMRI
(53% [33%; 69%] vs. 54%
[28%; 71%]; p = 0.75)
– Echocardiographically docu-
mented stable left ventricular wall
thickness (17 [13; 21] vs. 18 [14;
25] mm; p = 0.1)
– Echocardiographically docu-
mented stable MAPSE (10 [5; 23]
vs. 8 [4; 13] mm; p = 0.3)
Cappelli et al. 2018 (e10)
Single-center Pat. with ATTR-related Primary: – No survival advantage with EGCG Study discontinuation due Not licensed
study, retrospective cardiomyopathy Overall mortality (60 ± 15% [EGCG] vs. 61 ± 12% to diarrhea in 2 pat.,
– EGCG 675 mg/d for at [placebo], p = 0.276) no other AEs
least 9 months
EGCG
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
– n = 30 (EGCG: ATTRwt
n = 21, ATTRv n = 9) vs.
n = 35 (control group:
ATTRwt n = 30, ATTRv
n = 5)Deutsches Ärzteblatt International | Dtsch Arztebl Int 2020; 117: 159–66 | Supplementary material
Sub- Design Population/ Endpoints Effects and spread Adverse events Licensing status
stance/ observation period [95% confidence interval]
study
Phase III, ran- Cardiomyopathy in Primary: Study currently recruiting To be reported Not licensed
(NCT03481972)
domization, open- ATTRwt and ATTRv Efficacy of doxycycline/TUDCA
label study – 102 participants planned Overall mortality at 18 months
(doxycycline/ – Observation period
TUDCA vs. 30 months Secondary:
standard care) Overall mortality at 18 and 30 months
Phase II, single Pat. with symptomatic Primary: – 7 pat. tolerated 12 months, 10 pat. No SAEs; stomach ache, Not licensed
center, open-label neuronal or cardiac Treatment response (defined as mBMI reductionYou can also read
