Light Chain (AL) Amyloidosis: The Journey to Diagnosis

McCausland, Kristen L.; White, Michelle; Guthrie, Spencer; Quock, Tiffany P.; Finkel, Muriel; Lousada, Isabelle; Bayliss, Martha

doi:10.1007/s40271-017-0273-5

Cited by 89 publications

(100 citation statements)

References 11 publications

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“…Despite these advances, most patients with peripheral amyloidosis present with clinically advanced disease at which time significant tissue amyloid has been deposited and organ damage is manifest. In almost all cases, a diagnosis of amyloidosis results, albeit belatedly, from symptoms of cardiomyopathy, renal insufficiency, or peripheral neuropathy (28,29). For these patients, removal of amyloid deposits may stabilize or improve organ function.…”

Section: Discussionmentioning

confidence: 99%

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Wall

Williams

Foster

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting “peptope” comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4–mediated dissolution of a human AL amyloid extract implanted in mice.

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Section: Discussionmentioning

confidence: 99%

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Wall

Williams

Foster

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Patient may associate these symptoms with the ageing process or attribute them to other more prevalent chronic conditions. 27 These non-specific symptoms may not raise immediate concern for patients contributing to delays in seeking medical attention. Even in the presence of distinctive, but uncommon symptom, as purpura, 29 proper diagnosis of amyloidosis may be missed showing how difficult CA diagnosis could be.…”

Section: Protean Diseasementioning

confidence: 99%

Gateway and journey of patients with cardiac amyloidosis

et al. 2020

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Aims Advances have been made over the last decade in the management of cardiac amyloidosis (CA), but a delayed diagnosis is still common. The aim of this study was to describe the journey to CA diagnosis from initial clinical and to analyse time to diagnosis. Methods and results Between January 2001 and May 2019, 270 consecutive patients with CA diagnosed at Toulouse University Hospital were retrospectively included in this cross-sectional study: 111 (41%) light chain amyloidosis, 122 (45%) wild-type transthyretin amyloidosis, and 37 (14%) hereditary transthyretin amyloidosis. CA onset occurred mostly with dyspnoea (50%) or systematic follow-up (10%). The cardiologist was the first line specialist in 68% of patients, followed by the nephrologist (9%) and neurologist (8%). Patients encountered a median (minimum-maximum) number of two (1-7) physician specialists and performed a median (minimum-maximum) number of three (1-8) tests before diagnosis. Median delay between symptom onset and CA diagnosis was 8 [IQR 5-14], 10 [IQR 3-34], and 18 [IQR 4-49] months, respectively, in light chain amyloidosis, wild-type transthyretin amyloidosis, and hereditary transthyretin amyloidosis subgroups (P = .060). Having performed electromyography or spirometry was associated with a longer delay in diagnosis in the overall population: odds ratio = 1.13; 95% confidence interval 1.02 to 1.24; and odds ratio = 1.13; 1.03 to 1.24, respectively, probably due to non-specific initial symptoms. Conclusions CA is a protean disease with various first line specialists causing a diagnostic wandering despite increasing medical community awareness. It requires a multidisciplinary specialist care networks to educate and manage symptoms and therapies.

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“…Due to its non‐specific symptoms, delays in the diagnosis and misdiagnosis of AL amyloidosis are common 13 . McCausland et al 19 surveyed 341 patients and found that 62.5% (n = 213) were seen by greater than 3 physicians before receiving a definitive diagnosis. Another study by Lousada et al 20 utilized data from an online survey to describe the patient experience and journey.…”

Section: Introductionmentioning

confidence: 99%

Patient outcomes in light chain (AL) amyloidosis: The clock is ticking from symptoms to diagnosis

Schulman

Connors

Weinberg

et al. 2020

European J of Haematology

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Introduction Symptomology of AL amyloidosis can be vague, with a broad range of manifestations and potential etiologies. We sought to determine whether time from initial patient‐reported symptom onset to diagnosis was associated with survival. Methods The Boston University Amyloidosis Patient Database was queried for patients with AL amyloidosis who presented to the Center for initial evaluation from 2010 to 2015. Results A total of 324 patients with AL amyloidosis were evaluated for initial evaluation. The median time to diagnosis from initial symptom onset was 7.1 months (range, 0‐61). At data cutoff, 60.2% (n = 195) of patients were alive; of those, the majority were diagnosed <6 months from initial symptoms (52.3%, n = 102). In contrast, time to diagnosis from symptom onset was >6 months in 63.6% (n = 82) of patients who did not survive at the time of data cutoff (P = .0005). Survival analysis of time from diagnosis to death or data cutoff stratified by time from patient‐reported symptom onset to diagnosis (<6, 6‐12, and >12 months) showed significant differences among groups (P = .001). Additionally, multivariable regression demonstrated that an increase in time from self‐reported symptom onset to diagnosis was significantly associated with an increased risk of death (HR = 1.02, 95% CI = 1.01‐1.04, P = .002). Conclusion These results support the importance of early diagnosis for patients with AL amyloidosis.

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Light Chain (AL) Amyloidosis: The Journey to Diagnosis

Cited by 89 publications

References 11 publications

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Gateway and journey of patients with cardiac amyloidosis

Patient outcomes in light chain (AL) amyloidosis: The clock is ticking from symptoms to diagnosis

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