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Co-author Dr. Adebanke Adebayo presented our recent research about the ASB at the DC Health Communication Conference.

Our research topic:

Amyloidosis Speakers Bureau (ASB) patient narratives: Impact on information seeking behaviors among medical students

Background: According to Newman-Toker, et al. (2023), misdiagnosis–including missed, delayed, and wrong diagnoses–leads to an estimated 371,000 deaths and 424,000 permanent disabilities in the United States each year. In response to these alarming statistics, the Centers for Disease Control and Prevention (CDC, 2024), released a diagnostic toolkit that contains sections for patients, families, and caregivers. One difficult-to-diagnose disease is amyloidosis, a protein-misfolding disease. It’s hard to diagnose in part because it manifests in a variety of organs and its symptoms are similar to those of many other diseases, symptoms such as fatigue, shortness of breath, etc. In this study, patient engagement was highlighted as crucial to a correct diagnosis. Using Amyloidosis Speakers Bureau (ASB) patient educator presentations, this study explores the impact of patient educator presentations on information-seeking behaviors among medical students. The theoretical frameworks used to support this study are narrative and persuasion theories.

Methods: The Amyloidosis Speakers Bureau (ASB) arranges for amyloidosis patients to speak about their diagnostic and treatment experiences with U. S. medical students. Using a survey of U.S. medical students (N=1,634) and ASB health information mailings (N=50), we hypothesized that patients’ narratives about their diagnostic and treatment journeys would positively impact medical students’ information seeking behaviors about this disease.

Results: Participants who listened to an ASB patient speaker had significant higher means on information seeking behaviors, including the voluntary decision to sign-up to receive additional information from the ASB mailing list. Similarly, participants who listened to an ASB patient speaker were significantly more likely to open email information about amyloidosis–52.74%, than were people who received emailed health information from other organizations using distribution services like Mailchimp–20%.

Conclusions: Listening to a patient’s narrative presentation was associated with a high open rate for periodically emailed information on amyloidosis research by medical students who signed up to receive this information. We believe this study adds to the growing call-to-action to integrate patient narratives into medical curricula through platforms like the ASB. Future longitudinal studies should be conducted to explore the outcomes reported in this study over longer time frames.

The diagnosis of amyloidosis can be challenging for several reasons.

First and foremost, presenting symptoms are often nonspecific and common to other conditions that can send clinicians in multiple directions.
Second, due to the variability of presenting symptoms, rarely are two patient presentations identical.
Third, the diagnostic process requires (a) the confirmation of amyloidosis, and (b) the typing of amyloidosis, only after which can an appropriate treatment regimen be developed.

The perceived rarity of the disease itself gives providers pause to consider. Collectively, as a result of these reasons, diagnosis is often delayed and/or misdiagnosed, leading to devastating consequences for patients. Often, the key to diagnosis begins with developing a clinical suspicion.

DEVELOPING A CLINICAL SUSPICION FROM SYMPTOMS

The first step in diagnosing AL amyloidosis is to develop a clinical suspicion, done through connecting the seemingly random presenting symptoms.

As seen in the figure above, multiple pathologies are often present with AL amyloidosis¹. The most common is cardiac involvement, which also brings the highest mortality. Other common presentations range from nephropathy, including proteinuria (> 60% of patients), hepatomegaly (>50% of patients), neuropathy, whether autonomic (20% of patients) or peripheral (10-20% of patients), macroglossia (17% of patients), periorbital purpura (15% of patients) and GI manifestations (approximately 7% of patients).

Symptoms do not develop at the same time, nor in the same sequence from patient to patient. As a result, patients and providers often play “whack-a-mole,” going from specialist to specialist for specific symptoms. Misdiagnoses along the way are common, leading patients down paths that prove unproductive and, in some cases, counterproductive. This takes time, which is exactly what patients do not realize they do not have.

Suspicion of amyloidosis should be very high when a patient presents with heart failure combined with a constellation of unexplained extracardiac symptoms such as neuropathy, bleeding, carpal tunnel syndrome, nephrotic syndrome, proteinuria, diarrhea, hepatomegaly, peripheral and autonomic neuropathy, macroglossia, and periorbital purpura.¹

ALGORITHM FOR DIAGNOSING AL AMYLOIDOSIS¹

The figure below illustrates the current systematic, stepwise process for diagnosing amyloid light chain (AL) amyloidosis and differentiating it from other cardiomyopathies. It identifies each type of test that is essential for suspicion of AL amyloidosis, diagnosing the disease and typing of the amyloidogenic free light chains (FLCs).

ACR = albumin/creatinine ratio

DPD = 99mTc-3-diphosphono-1,2-propanodicarboxylic acid

Echo = echocardiography

EKG = electrocardiography

LFT = liver function test

MRI = magnetic resonance imaging

NT-proBNP = N-terminal pro–brain natriuretic peptide

PYP = 99mTc-pyrophosphate

SIFE = serum immunofixation electrophoresis

UIFE = urine immunofixation electrophoresis

TYPING AND CONFIRMING DIAGNOSIS¹

Once the presence of amyloid has been confirmed, it is imperative to next identify the type of amyloid fibril in order to avoid misdiagnosis and initiation of incorrect or inappropriate treatment, which could have disastrous consequences for a patient.

The most common methods of amyloid fibril typing include immunohistochemistry or laser capture, followed by mass spectrometry. As the accuracy of immunohistochemistry is dependent on the expertise of the laboratory and needs an extensive panel of antibodies for accurate reporting, laser capture with mass spectrometry has become the method of choice for amyloid fibril typing.

Despite advances in noninvasive imaging, tissue biopsy remains a common and important confirmational step in most cases.

Once a diagnosis of amyloidosis has been confirmed, along with the specific type, an appropriate treatment regime can then be determined.

CONCLUSION – WHY EARLY DIAGNOSIS MATTERS

With AL amyloidosis, time is of the essence for patients. This is an aggressive disease where early treatment intervention can truly extend lives and improve QoL. As recently as the 1990s, this was considered a terminal disease with a high mortality rate, often offering patients months to a few years to live. With earlier diagnosis and advancements in treatments, survival is extending and QoL is improving.

IN CLOSING

The key take-aways are two-fold: (1) when confronted with multiple unexplained symptoms, suspect multi-system diseases like amyloidosis, and (2) remember that early diagnosis is key for patient survival.

For more detail on diagnosing and treating AL amyloidosis, please see the paper referenced below.

Source:

⁽¹⁾Wechalekar, A, Fontana, M, Quarta, C. et al. AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review. J Am Coll Cardiol CardioOnc. 2022 Nov, 4 (4) 427–441.

https://doi.org/10.1016/j.jaccao.2022.08.009

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Bill. He discusses the challenges physicians may face in interpreting issues their patients face – it may not always be easy.

WHAT IS IT?

According to the NIH ⁽¹⁾, macroglossia is the abnormal enlargement of the tongue in proportion to other structures in the mouth. It usually occurs secondary to an underlying disorder that may be present from birth (congenital) or acquired.

SYMPTOMS

Symptoms associated with macroglossia may include drooling, speech impairment, difficulty eating, noisy and/or high-pitched breathing (stridor), snoring, airway obstruction, abnormal growth of the jaw and teeth, and ulceration. In some cases, the tongue may protrude from the mouth. ⁽¹⁾⁽³⁾

Talking may be affected. The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth. Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder. ⁽³⁾

In addition to an enlarged tongue it is common to see indentations around the tongue perimeter from the constant pressure against the teeth.

Patients who graciously offered their picture for this blog reinforce many of these symptoms, including TMJ, difficulty swallowing, and breathing. Reiterated almost unanimously, eating is a problem – chewing and swallowing, clearing food from their mouth. Food gets stuck in front of their teeth. Speech is affected, and they often sound “slushy.” Snoring can get so bad it wakes them (and partners) up during the night. In addition, sometimes, their tongue gets sore from rubbing against their teeth.

WHAT CAUSES IT?

Macroglossia can be associated with a wide range of congenital (present from birth) and acquired conditions (e.g., malignancies, metabolic/endocrine disorders, inflammatory or infectious diseases; amyloidosis), or it can occur as an isolated feature (with no other abnormalities). In most cases, it is due to vascular malformations (blood vessel abnormalities) and muscular hypertrophy (an increase in muscle mass). ⁽¹⁾

Macroglossia is the most frequent oral manifestation of amyloidosis and may be found as the only presenting symptom of the disease or included in a longer list of other symptoms. In addition, while occurring much more frequently in AL Light Chain amyloidosis, it can also accompany hereditary ATTR Transthyretin amyloidosis. ^{(2, 4)}

HOW IS IT TREATED?

There is no cure, but treatments can manage the symptoms. Treatment depends upon the underlying cause and severity and may range from speech therapy in mild cases, to orthodontic procedures, to surgical reduction in more severe cases. ^{(1) (3)}

Sources

National Institutes of Health
NIH National Library of Medicine
National Organization for Rare Disorders
https://ashpublications.org/blood/article/116/21/5007/66459/Macroglossia-Not-Always-AL-Amyloidosis

Ref 5 (picture only)

https://www.mayoclinic.org/diseases-conditions/amyloidosis/multimedia/enlarged-tongue/img-20008056

Transthyretin (TTR) is a protein, mainly produced by the liver. The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. ₍₂₎ In the case of Transthyretin Amyloidosis, TTR proteins (in the form of a tetramer) separate into individual monomers and become misfolded. The misfolded proteins aggregate into amyloid fibrils which deposit throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastrointestinal, etc. in nature.

The two main types of ATTR are Wild Type and Hereditary. Wild Type Amyloidosis is a disorder predominately of older men in their 70s and beyond. Hereditary Amyloidosis is associated with an inherited genetic mutation.

The four main types of treatments for ATTR, either currently available or in development, consist of stabilizers, silencers, depleters, and gene editors. Note the treatments discussed below include those that are FDA-approved at the time of writing; new FDA-drugs will likely become available in the future.

Stabilizers

TTR stabilization therapy aims to prevent misfolding/destabilization of TTR as shown circled in blue on the illustration below.

There are several TTR stabilization therapies available, including acoramidis, tafamidis, and diflunisal.

Acoramidis (AG10) binds to TTR at thyroxine binding sites and slows dissociation of the TTR tetramer. ₍₅₎Acoramidis was approved by the FDA in 2024 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, twice per day.

Tafamidis binds to the TTR and stabilizes the TTR tetramer, thus slowing misfolding and inhibiting the formation of amyloid fibrils. ₍₄₎Tafamidis was FDA approved in 2019 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, once per day.

Diflunisal is a non-steroid anti-inflammatory (NSAID) drug, primarily used to treat pain associated with arthritis, but can be used “off-brand” as a TTR stabilizer. A study proved that diflunisal prevented amyloid fibril formation by tying TTR binding sites in a similar manner to tafamidis. Diflunisal has been shown to halt disease progression and improve quality of life. ₍₃₎

Silencers

In the case of hereditary amyloidosis, TTR silencer therapy aims to prevent destabilization of TTR by silencing errant “messenger RNA” signals. There are multiple silencing therapies available, including patisiran,vutrisiran, inotersen, and eplontersen.

An illustration of the silencing process associated with vutisiran is shown below. The process utilizes small interfering RNAs (siRNA) which results in a single stranded RNA which cleaves the messenger RNA, thus destroying it. ₍₇₎₍₈₎

Vutisiran is a newer version of patisiran. It is given as an injection once every three months and must be administered at a healthcare facility. Vutisiran is currently FDA approved for ATTR with polyneuropathy, however, recent clinical trial results show promising data associated with treatment of cardiomyopathy.

Eplontersen is a newer version of inotersen and is FDA approved for polyneuropathy. It can be self-administered monthly via an auto-injector at home. A clinical trial for its use in the treatment of cardiomyopathy is ongoing.

Since TTR proteins serve to transport retinol, a vitamin A supplement must be prescribed to patients using silencer therapy.

Depleters

Also known as antibody therapies, there are a number of treatments currently under development that are designed to remove amyloid that has been deposited in bodily organs and tissue, including

ALXN-2220, AT02, NNC6019.

For example, ALXN-2220 is an investigational antibody that incorporates a fundamental mechanism of the human immune system. The ALXN-2220 antibody specifically targets insoluble ATTR fibrils, eliminating ATTR by activating immune cells which ingest and destroy cellular debris. ₍₆₎

Gene Editors

In the field of genome engineering, the term “CRISPR” is often used loosely to refer to the various systems that can be programmed to target specific stretches of genetic code and to edit DNA at precise locations. With this system, genes in living cells are permanently modified, allowing for the correction of mutations at precise locations in the human genome. ₍₉₎

CRISPR NTLA-2001 is a form of gene editing, currently in clinical trial, that is designed to edit mutated DNA associated with hereditary amyloidosis. This therapy would be a one-time treatment to remove the area of the DNA with the mutation in the liver cells producing the TTR.

… And More

Looking ahead, research of new treatments is active and exciting. The future looks brighter than ever for ATTR patients!

For further information on this paper’s subject matter, please view:

ATTR Amyloidosis Treatments: Stabilizers and Silencers

CRISPR/Cas9 – Editing the Code of Life

Bibliography

Sperry, Brett, “Expert Insights Into Amyloidosis, ATTR Amyloidosis Treatments: Stabilizers and Silencers,” Amyloidosis Speakers Bureau, 2024. https://drive.google.com/file/d/1qoAETBYDjDj3zHzxqqxHvAfoq1sfiuEd/view

“Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis

Morfino, P., Aimo, A., Vergaro, G., Sanguinetti, C., Castiglione, V., Franzini, M., Perrone, M. A., & Emdin, M. (2023). Transthyretin stabilizers and seeding inhibitors as therapies for amyloid transthyretin cardiomyopathy. Pharmaceutics, 15(4), 1129. https://doi.org/10.3390/pharmaceutics15041129

Coelho, T., Merlini, G., Bulawa, C. E., Fleming, J. A., Judge, D. P., Kelly, J. W., Maurer, M. S., Planté-Bordeneuve, V., Labaudinière, R., Mundayat, R., Riley, S., Lombardo, I., & Huertas, P. (2016, June). Mechanism of action and clinical application of Tafamidis in hereditary transthyretin amyloidosis. Neurology and therapy. https://pmc.ncbi.nlm.nih.gov/articles/PMC4919130/

National Institutes of Health. (n.d.). DailyMed – ATTRUBY- acoramidis hydrochloride tablet, film coated. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=913552ef-875d-4cb7-bf05-a7d20a394c38

Michalon, A., Renaud, L., Machacek, M., Cortijo, C., Udata, C., Mercuri, M. F., Buller, F., Hock, C., Nitsch, R. M., Kahr, P. C., & Grimm, J. (2024). Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling. Clinical Pharmacology and Therapeutics, 117(1), 261. https://doi.org/10.1002/cpt.3455

“What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.

“RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai

Questions and answers about CRISPR. @broadinstitute. (2014, December 17). https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr

Dr. Morie Gertz, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, talks about how the immune system can be harnessed in the fight against amyloidosis and multiple myeloma. He discusses two immune-directed therapies: CAR-T and Bispecific Antibodies. Dr. Gertz eloquently, and in an easy-to-understand way, summarizes the goal of immune-directed therapies and the two approaches today, including the processes, outcomes, advantages, and risks to be considered. This is a must-watch video for physicians from a legendary expert.

The Amyloidosis Speakers Bureau (ASB), founded in 2019, arranges for ASB patient educators to speak about their diagnostic and treatment experiences with medical students. In 2023, we published a study to understand the impact from the addition of the patient voice to didactic medical education. The study concluded that listening to an ASB patient educator’s narrative was associated with positive attitudes toward communication with patients, interest in acquiring and applying knowledge of amyloidosis, and humility about diagnosis. Post-publishing, continued analysis of the presentation feedback made it clear that another benefit was occurring. During the ASB presentations, questions were repeatedly raised about what guidance the patients might offer to help these budding doctors become better providers and how they could improve their relationships with patients. Their inquiries had nothing to do with amyloidosis and were relevant to every interaction and all diseases. These future providers wanted to be better and wanted the patient’s perspective to help get there. Assessing their questions revealed an unexpected benefit from the patient presentations.

LINK TO ARTICLE

In this video “Amyloidosis Awareness” from the Amyloidosis Support Groups, narrated by Michael York you’ll hear a brief yet comprehensive overview of amyloidosis designed specifically for patients. It discusses what amyloidosis is, the wide range of symptoms, and which organs are typically involved. It focuses on the most common types, AL (light chain) and TTR (transthyretin), and summarizes the kinds of treatments that are currently available.

Dr. Brett Sperry, cardiologist and director of the Cardiac Amyloidosis Program at Saint Luke’s Mid America Heart Institute, provides an excellent overview of FDA-approved ATTR amyloidosis treatments. He goes into detail about the biology behind silencers and stabilizers and exactly how they impair amyloidosis progression. In addition, he previews the future, summarizing new categories of drugs on the horizon.

Update: In November, 2024 the FDA approved Attruby (Acoramidis) for ATTR-CM (wild-type and hereditary/variant).

The future is indeed exciting!

Attruby (Acoramidis), was approved by the FDA on November 22, 2024 for ATTR-CM patients (both wild-type and hereditary) in the U.S.

Orally-administered, Attruby is a near complete TTR stabilizer (>= 90%), designed to reduce cardiovascular death and cardiovascular-related hospitalization. In addition, Attruby has been shown to preserve the native function of TTR as a transport protein of thyroxine and vitamin A.

To honor the courage of our U.S. clinical trial participants, BridgeBio will provide these patients Attruby free for life.

Attruby

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ASB Research Presented at DC Health Communication Conference!

AL Amyloidosis: Diagnosis Begins With Suspicion

Patient Insights: Interpreting a Patient’s Issues