Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy

Adams, David H.; Ando, Yukio; Beirão, João Melo; Coelho, Teresa; Gertz, Morie A.; Gillmore, Julian D.; Hawkins, Philip N.; Lousada, Isabelle; Suhr, Ole B.; Merlini, Giampaolo

doi:10.1007/s00415-019-09688-0

Cited by 175 publications

(225 citation statements)

References 83 publications

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“…In clinical practice, it is critical to distinguish between treatable versus non-treatable amyloidoses. Moreover, amyloidoses with a genetic component must be distinguished from the sporadic types and systemic amyloidoses must be distinguished from the localized forms [5][6][7][8][9][10][11][12]. AL, amyloidosis derived from immunoglobulin light chain, has been considered, thus far, the most common form of systemic amyloidosis in the developed world [6,7,12,13].…”

Section: Classificationmentioning

confidence: 99%

“…Hereditary amyloidosis caused by mutations in the TTR gene (TTRv, variant) has begun to emerge as a significantly underdiagnosed cause of cardiac failure and polyneuropathy [8][9][10]12]. The worldwide prevalence of ATTRv is estimated at 50,000 individuals, with varying phenotypic presentations [29].…”

Section: Hereditary Amyloidosesmentioning

confidence: 99%

“…Determination of the amyloid protein type is imperative before specific therapy can be implemented [5][6][7][8][9][10][11][12]. There is significant heterogeneity in the spatial distribution of amyloid in various tissues and, while there is some predilection of certain amyloid types for particular organs, the determination of the amyloid type on clinical grounds alone is not reliable; the amyloid protein type must be determined by immune and/or proteomic examination of the actual amyloid deposits.…”

Section: Amyloid Typingmentioning

confidence: 99%

“…While immunofluorescence in frozen sections and immunohistochemistry in paraffin sections have traditionally been used for amyloid typing, mass spectrometry has emerged as the method of choice for the typing of amyloid proteins, in particular in paraffin sections [6][7][8][9][10][11][12][62][63][64][65][66][67][68][69][70][71][72].…”

Section: Amyloid Typingmentioning

confidence: 99%

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The Pathology of Amyloidosis in Classification: A Review

2020

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Background: The amyloidoses are a rare and heterogeneous group of disorders that are characterized by the deposition of abnormally folded proteins in tissues ultimately leading to organ damage. The deposits are mainly extracellular and are recognizable by their affinity for Congo red and their yellow-green birefringence under polarized light. Current classification of amyloid in medical practice is based on the amyloid protein type. To date, 36 proteins have been identified as being amyloidogenic in humans. Summary: in clinical practice, it is critical to distinguish between treatable versus non-treatable amyloidoses. Moreover, amyloidoses with a genetic component must be distinguished from the sporadic types and systemic amyloidoses must be distinguished from the localized forms. Among the systemic amyloidoses, AL continues to be the most common amyloid diagnosis in the developed world; other clinically significant types include AA, ALECT2, and ATTR. The latter is emerging as an underdiagnosed type in both the hereditary and wild-type setting. Other hereditary amyloidoses include AFib, several amyloidoses derived from apolipoproteins, AGel, ALys, etc. In a dialysis setting, systemic amyloid derived from β 2 microglobulin (Aβ2M) should be considered, although a very rare hereditary variant has also been reported; several amyloido-ses may be typically associated with aging and several iatrogenic types have also emerged. Determination of the amyloid protein type is imperative before specific therapy can be implemented and the current methods are briefly summarized. A brief overview of the target organ involvement by amyloid type is also included. Key Messages: (1) Early diagnosis of amyloidosis continues to pose a significant challenge and requires the participation of many clinical and laboratory specialties. (2) Determination of the protein type is imperative before specific therapy can be implemented. (3) While mass spectrometry has emerged as the preferred method of amyloid typing, careful application of immune methods is still clinically useful but caution and experience, as well as awareness of the limitations of each method, are necessary in their interpretation. (4) While the spectrum of amyloidoses continues to expand, it is critical to distinguish between those that are currently treatable versus those that are untreatable and avoid causing harm by inappropriate treatment.

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Section: Classificationmentioning

confidence: 99%

Section: Hereditary Amyloidosesmentioning

confidence: 99%

Section: Amyloid Typingmentioning

confidence: 99%

Section: Amyloid Typingmentioning

confidence: 99%

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The Pathology of Amyloidosis in Classification: A Review

2020

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“…Recent expert consensus recommendations to improve diagnosis of TTR amyloidosis with polyneuropathy were published to avoid confusion with CIDP, idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. 16 The challenge in recognition of TTR amyloidosis is more prominent in non-endemic areas, namely outside Portugal, Japan, Sweden, and Brazil. A high index of suspicion is required.…”

Section: Discussionmentioning

confidence: 99%

Transthyretin Familial Amyloid Polyneuropathy Mimicking Chronic Inflammatory Demyelinating Polyneuropathy

Thuringer

Jawdat

Dimachkie

2020

rrnmf

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Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Coelho,

Marques,

Dasgupta

et al. 2023

JAMA

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ImportanceTransthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.ObjectiveTo evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and ParticipantsNEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group.InterventionsSubcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and MeasuresPrimary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.ResultsAmong 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P &lt; .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P &lt; .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P &lt; .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and RelevanceIn patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10

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Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy

Cited by 175 publications

References 83 publications

The Pathology of Amyloidosis in Classification: A Review

The Pathology of Amyloidosis in Classification: A Review

Transthyretin Familial Amyloid Polyneuropathy Mimicking Chronic Inflammatory Demyelinating Polyneuropathy

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

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