New hATTR-PN guidelines call for earlier diagnosis, faster treatment
International experts emphasize coordinated care and regular monitoring
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An international team of experts has published new guidelines for diagnosing and treating hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and forms of the disease that affect both the nerves and heart.
The recommendations “underscore the critical importance of early diagnosis, provide guidance on proactive monitoring pre-symptomatic patients and carriers, early intervention, and coordinated multidisciplinary care,” the researchers wrote. “Implementation of the proposed recommendations has the potential to reduce diagnostic delay, improve care coordination, and ultimately optimize long-term outcomes for individuals living with ATTR amyloidosis.”
New guidelines address gaps in hATTR-PN care
The guidelines were described in the study “Diagnosis and management of transthyretin amyloidosis (ATTRv) across ATTRv-PN and mixed phenotype: an international delphi consensus,” whose early-access version was published in BMC Neurology. The work was funded by AstraZeneca, which markets the hATTR-PN-approved treatment Wainua (eplontersen).
Hereditary transthyretin amyloidosis (hATTR or ATTRv) refers to a group of progressive genetic conditions caused by mutations in the TTR gene, which provides instructions for making the transthyretin protein. These mutations cause the protein to misfold and form harmful clumps, called amyloid deposits, that build up and damage tissues and organs.
hATTR is typically divided into two main forms: hATTR-PN, which damages the nerves outside the brain and spinal cord, and hereditary ATTR-CM, which mainly affects the heart.
However, many patients have symptoms affecting both the heart and nerves. The researchers cited evidence suggesting that “up to 80% of patients with ATTRv … have a mixed phenotype [profile] with both [heart] and neurologic symptoms.” They also noted that “Limited guidelines exist for the diagnosis and management of patients with ATTRv-PN … and ATTRv … with a mixed phenotype.”
To address these gaps, four hATTR experts from the U.S., Canada, and the U.K. developed 45 proposed recommendations on diagnosing and treating hATTR-PN and mixed-phenotype hATTR.
International survey finds broad agreement among specialists
The team then sent the 45 proposed recommendations to specialists in seven countries for feedback. They received completed surveys from 100 clinicians. Most were neuromuscular neurologists (74%), while 62% had at least 11 years of experience in their roles. Nearly half (49%) managed at least 16 patients with hATTR-PN or mixed-phenotype hATTR each year.
At least 75% of the surveyed clinicians agreed with 43 of the 45 proposed recommendations. The other two did not reach that level of agreement. Based on these results, the researchers developed seven broader recommendations for diagnosing, treating, and managing hATTR-PN and mixed-phenotype hATTR.
The recommendations call for early genetic testing in people with progressive or unexplained nerve damage. They also recommend testing people ages 60 and older with carpal tunnel syndrome affecting one or both wrists, when the condition is not explained by a rheumatic disease, work-related exposure, or injury. Carpal tunnel syndrome affects a nerve in the wrist and can be an early warning sign of hATTR-PN.
The experts also recommend assessing nerve and heart symptoms together. They stress the importance of specific laboratory tests to rule out light chain (AL) amyloidosis, a related disease caused by the buildup of clumps of a different protein.
The experts recommended referring people diagnosed with hATTR-PN or mixed-phenotype hATTR to specialized care centers. However, the initial evaluation should not be delayed while waiting for a specialist referral. Genetic testing should also be offered to patients’ blood relatives.
Experts recommend prompt treatment and regular monitoring
The guidelines recommend starting disease-modifying treatment in patients with symptomatic hATTR-PN or mixed-phenotype hATTR as soon as possible, within one month of diagnosis. The goal is to slow disease progression.
In the U.S., three therapies are currently approved for hATTR-PN. The recommendations advise doctors to consider “efficacy, safety, [co-occurring health conditions], and personal preferences of the patient” when choosing a treatment. The experts recommend gene-silencing therapies — Onpattro (patisiran), Amvuttra (vutrisiran), or Wainua — as first-line treatment for patients with hATTR-PN or mixed-phenotype hATTR who have neurologic symptoms.
After treatment begins, patients should be monitored every three to six months, depending on disease severity, “with additional testing … as needed,” the researchers wrote. Neurologists and cardiologists should also work together to coordinate patients’ care.
The guidelines also recommend yearly monitoring for people who carry a disease-causing mutation but have no symptoms. Monitoring should begin 10 years before symptoms are expected to appear, based on family history.
To help doctors follow these recommendations, the researchers also developed a checklist covering diagnosis, treatment, and ongoing care.
“The consensus achieved broad alignment with previous expert recommendations relating to early diagnosis, multidisciplinary management, disease-modifying treatment, and ongoing monitoring, while extending existing guidance through the inclusion of a large international multidisciplinary panel and the development of a practical clinical checklist,” the researchers wrote.
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