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Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

BMC Musculoskeletal Disorders volume 24, Article number: 751 (2023) Cite this article

Abstract

Background

Hereditary and wild-type transthyretin-mediated (ATTRv and ATTRwt) amyloidoses result from the misfolding of transthyretin and aggregation of amyloid plaques in multiple organ systems. Diagnosis of ATTR amyloidosis is often delayed due to its heterogenous and non-specific presentation. This review investigates the association of musculoskeletal (MSK) manifestations with ATTR amyloidosis and the delay from the onset of these manifestations to the diagnosis of ATTR amyloidosis.

Methods

This systematic review utilized Medline and EMBASE databases. Search criteria were outlined using a pre-specified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included: amyloidosis, ATTR, and MSK manifestations. Publication quality was assessed utilizing Joanna Briggs Institute (JBI) critical appraisal checklists.

The search initially identified 7,139 publications, 164 of which were included. PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis. 163 publications reported on ATTR amyloidosis and MSK manifestations, and 13 publications reported on the delay in ATTR amyloidosis diagnosis following the onset of MSK manifestations.

Results

The MSK manifestation most frequently associated with ATTR amyloidosis was carpal tunnel syndrome (CTS); spinal stenosis (SS) and osteoarthritis (OA), among others, were also identified. The exact prevalence of different MSK manifestations in patients with ATTR amyloidosis remains unclear, as a broad range of prevalence estimates were reported. Moreover, the reported prevalence of MSK manifestations showed no clear trend or distinction in association between ATTRv and ATTRwt amyloidosis.

MSK manifestations precede the diagnosis of ATTR amyloidosis by years, and there was substantial variation in the reported delay to ATTR amyloidosis diagnosis. Reports do suggest a longer diagnostic delay in patients with ATTRv amyloidosis, with 2 to 12 years delay in ATTRv versus 1.3 to 1.9 years delay in ATTRwt amyloidosis.

Conclusion

These findings suggest that orthopedic surgeons may play a role in the early diagnosis of and treatment referrals for ATTR amyloidosis. Detection of MSK manifestations may enable earlier diagnosis and administration of effective treatments before disease progression occurs.

Peer Review reports

Introduction

Background

Systemic amyloidoses are protein-misfolding diseases characterized by the aggregation and deposition of amyloid plaques in multiple organ systems [1, 2]. Transthyretin-mediated (ATTR) amyloidosis is caused by misfolding of the precursor protein transthyretin (TTR) [1, 2]. There are two types of ATTR amyloidoses, variant (ATTRv) [also known as hereditary or hATTR] and wild-type (ATTRwt) [2, 3]. In ATTRv amyloidosis, point variants in the TTR gene lead to destabilization and dissociation of TTR from its native tetrameric conformation, and subsequent aggregation as amyloid fibrils [4]. In ATTRwt amyloidosis, wild-type, non-variant TTR dissociates, and amyloid aggregation occurs [4]. ATTRwt and ATTRv amyloidoses overlap in their clinical presentation, and therefore, definitive distinction relies on TTR gene sequencing in suspected patients [2]. ATTRv amyloidosis affects approximately 50,000 people worldwide. While the exact prevalence of ATTRwt amyloidosis is unknown, it is thought to be more prevalent than ATTRv amyloidosis [1, 5].

ATTR amyloidosis is a heterogeneous, multisystem disease in which a significant proportion of patients develop a mixed phenotype of polyneuropathy (PN) and cardiomyopathy (CM) [2, 5, 6]. The disease is rapidly progressive; ATTRv and ATTRwt amyloidoses have a median survival of 4.7 years and 3.6 years after diagnosis, respectively, and disease progression substantially negatively impacts quality of life [5, 7, 8]. Diagnosis can be difficult or delayed due to the heterogenous, non-specific nature of ATTR amyloidosis and symptom overlap with other diseases [9,10,11]. Various musculoskeletal (MSK) manifestations, such as carpal tunnel syndrome (CTS), spinal stenosis (SS), osteoarthritis (OA), and others, have been reported in patients with ATTR amyloidosis [1]. Importantly, these MSK manifestations have been shown to precede the diagnosis of the disease by years [1, 4, 11].

Rationale

The typical patient journey before being diagnosed with ATTR amyloidosis is lengthy and involves consulting numerous physicians from different specialties [2, 11]. Consequently, ATTR amyloidosis may remain undetected, and treatment is often delayed until the disease progresses to an advanced stage. This diagnostic delay increases patient disability and morbidity, whereas earlier therapeutic intervention can attenuate disease progression and worsening in patient quality of life. [2]. Enabling earlier diagnosis of ATTR amyloidosis is critical to improving overall patient prognosis [1]. Various MSK manifestations have been reported in the literature to be associated with ATTR amyloidosis. Additionally, certain manifestations, such as CTS, symptoms of which can also be caused by the PN of ATTR amyloidosis, are already included among the early signs, which are considered ‘red flags’ for the disease.

This systematic review was conducted to investigate the association between ATTR amyloidosis and MSK manifestations, and to investigate the temporal association between the onset of MSK manifestations and ATTR amyloidosis diagnosis.

Methods

Search strategy and criteria

The protocol for this systematic review is registered on the international prospective register of systematic reviews (PROSPERO) from the National Institute for Health Research Database (www.crd.york.ac.uk/prospero; protocol no. CRD42022310956), and the PRISMA statement was adhered to [12].

An electronic database search was run on November 3, 2021 across two databases in Ovid®: Medline and EMBASE. No restriction on publication year was applied. Search strategies are detailed in Supplement 1.

Gray literature searches included hand searches of previously published systematic reviews and a review of conference proceedings from 2019 to 2021. Independent hand searches of conference proceedings were conducted for the American Association for Hand Surgery (AAHS), American Society for Surgery of the Hand (ASSH), European Society of Cardiology (ESC), European ATTR amyloidosis meeting (EU-ATTR), Federation of European Societies for the Surgery of the Hand (FESSH), International Federation of Societies for Surgery of the Hand (IFSSH), International Society of Amyloidosis (ISA), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Conferences of interest that were not independently hand searched, given that the EMBASE electronic database search already captured their proceedings, included the American College of Cardiology (ACC), Heart Failure Society of America (HFSA), and the Peripheral Nerve Society (PNS).

Inclusion and exclusion criteria

The inclusion and exclusion criteria were pre-defined in a patient, intervention, comparator, outcome, time, study (PICOTS) table during protocol development (Supplement 2). These included outcomes related to the epidemiology, pathophysiology, temporal association (the time from the diagnosis of the MSK manifestation(s) to the diagnosis of ATTR amyloidosis), clinical burden, and current clinical practice related to MSK manifestations associated with ATTR amyloidosis. Publications reporting data only from patients diagnosed with amyloidoses other than ATTR amyloidosis were excluded, as were publications reporting on outcomes related to MSK manifestations outside of an ATTR amyloidosis context and/or publications reporting separately on either ATTR amyloidosis or MSK manifestations. Case series were included, while case reports involving individual patients were excluded [13]; for the list of those case reports by MSK manifestation, refer to Supplement 3.

All abstracts and full texts included were screened by two separate reviewers. Conflicts on inclusion or exclusion were resolved by a third senior reviewer.

Of the 7,139 publications identified, 164 publications were included in the analysis, as shown in the PRISMA diagram, (Fig. 1). Importantly, authors of the publications included approached the association between MSK manifestations and presence of ATTR amyloidosis differently. For example, some authors investigated MSK manifestations in patients with a confirmed diagnosis of ATTR amyloidosis, whereas other authors investigated the presence of ATTR amyloidosis in patients who had undergone treatment for MSK manifestations or who were diagnosed with a MSK manifestation, presented in Table 1.

Fig. 1
figure 1

PRISMA flow diagram of the study identification and screening process. ASSH = American Society for Surgery of the Hand; ESC = European Society of Cardiology; EU-ATTR = European transthyretin-mediated amyloidosis meeting; FESSH = Federation of European Societies for Surgery of the Hand; n = number; ISA = International Society of Amyloidosis; ISPO = International Society for Pharmacoeconomics and Outcomes Research; PNS = Peripheral Nerve Society; SLR = systematic literature review

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Table 1 Cross-tabulation of the number of publications investigating the association between ATTR amyloidosis and MSK manifestations, and the direction of the association reported
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One hundred sixty-three publications examined the association between MSK manifestations and ATTR amyloidosis (Fig. 2 provides an overview of studies and Tables 2, 3, 4, 5, 6 and 7 provide study details), and 13 publications investigated the temporal association between MSK manifestations and ATTR amyloidosis (Fig. 3 with study details reported in Table 8). One publication reported only on the temporal delay and did not report on the association between MSK manifestations and ATTR amyloidosis.

Fig. 2
figure 2

Number of publications reporting on various MSK manifestations associated with ATTR amyloidosis. Eight other publications reported on the association between ATTR amyloidosis and several different MSK manifestations in various combinations, the details of which are reported in Table 7

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Fig. 3
figure 3

Time between MSK symptom onset and ATTR amyloidosis diagnosis

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Table 2 Carpal tunnel syndrome in patients with ATTR amyloidosis
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Table 3 ATTR amyloidosis in patients with carpal tunnel syndrome
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Table 4 Spinal stenosis in patients with ATTR amyloidosis, and ATTR amyloidosis in patients with spinal stenosis
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Table 5 Carpal tunnel syndrome and or spinal stenosis in patients with ATTR amyloidosis
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Table 6 ATTR amyloidosis in patients with osteoarthritis, and ATTR amyloidosis in patients with osteoarthritis
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Table 7 ATTR amyloidosis in patients where more than one musculoskeletal manifestation was reported and multiple musculoskeletal manifestations in patients with ATTR amyloidosis
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Table 8 Temporal association between MSK manifestation onset and ATTR amyloidosis diagnosis
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Assessment of study quality

A quality assessment of the included publications was performed by one reviewer (and cross-checked by a second to ensure accuracy with discrepancies settled by a third senior reviewer) using the most appropriate Joanna Briggs Institute (JBI) critical appraisal checklist. This assessment was conducted at the publication level [179].

Following the JBI quality assessment of the 163 publications examining the association between MSK manifestations and ATTR amyloidosis, 51 publications were identified as being at low risk of bias [179]. 87 publications had at least one quality domain that implied some potential bias. The most common reason was limited reporting on the method of participant selection and method of diagnosis. In the 25 remaining publications, insufficient information was reported to measure the potential risk of bias.

Of the 13 publications examining the temporal association, four were found to have a low risk of bias, seven had at least one quality domain that implied some potential bias, and in the remaining two publications, there was insufficient information reported to measure the potential risk of bias.

Data collection and data extraction

The following information from each included publication was extracted: (1) publication characteristics: title, author, publication year, study design, objectives, country, and data collection period, (2) population characteristics: ATTR amyloidosis diagnosis, MSK manifestation subgroup, sample size, and demographic data such as age and sex, (3) the direction of the association relationship (ATTR amyloidosis outcomes in patients with MSK manifestations or MSK manifestations outcomes in patients with ATTR amyloidosis), (4) outcomes as defined in the PICOTS criteria (Supplement 2). Each independent reviewer piloted the data extraction form, and discussions were held to inform any necessary refinements. Data extraction was performed by one reviewer and cross-checked by a second to ensure accuracy. Discrepancies were settled by a third senior reviewer.

Results

What evidence supports the association between ATTR amyloidosis and MSK manifestations?

Most studies reported an association between ATTR amyloidosis and CTS (Tables 2 and 3); however, SS, OA, biceps tendon rupture (BTR), rotator cuff injury (RCI), and trigger finger (TF) were also reported and those studies are detailed in Tables 4, 5, 6 and 7. The association between MSK manifestations and the presence of ATTR amyloidosis were reported bi-directionally; for example, some authors investigated CTS in patients with a confirmed diagnosis of ATTR amyloidosis (Table 2), whereas other authors investigated the presence of ATTR amyloidosis in patients who had undergone treatment for CTS (Table 3). When case series were excluded, the prevalence of CTS in patients with ATTR amyloidosis (inclusive of ATTRv and ATTRwt) ranged between 0.5 and 80% (Table 2) [17, 100], and the prevalence of ATTR amyloidosis (inclusive of ATTRv and ATTRwt) in patients with CTS and/or a history of carpal tunnel release (CTR) surgery ranged between 0.9 and 38% (Table 3) [106, 122]. The prevalence of ATTRv amyloidosis in patients with a history of CTR surgery was higher, at 87.5% [113]. Due to the heterogeneity of the studies’ methodologies and approaches, it is not possible to directly compare the prevalences reported. Two publications investigated the prevalence of ATTRv and ATTRwt amyloidoses separately in the same cohort of patients with CTS, finding that ATTRwt amyloidosis was more prevalent in both instances [106, 110].

The prevalence range for SS in patients with ATTR amyloidosis (inclusive of ATTRv and ATTRwt) was narrower than the range reported for CTS, at 8.4–22.0% [123, 124] (Table 4). As observed with CTS, the range of prevalence of ATTR amyloidosis in patients with SS was broader than the range of SS prevalence in patients with ATTR amyloidosis, at 5.0–45.3% (Table 4) [125,126,127,128,129,130,131]. Where patients with ATTRwt amyloidosis were the focus, the prevalence of SS ranged between 19.0 and 45.3% [130, 131]. Comparably, Cortese et al. found that in a cohort of patients with ATTRv amyloidosis, 22.0% of patients had previously been diagnosed with SS [124]. In reports where the prevalence of both CTS and SS was explored in the same cohort of patients with ATTR amyloidosis (Table 5), CTS was more prevalent than SS in patients with ATTRv amyloidosis [134,135,136, 143, 147], as well as in patients with ATTRwt amyloidosis [139].

Several studies investigated ATTR amyloidosis in OA [153,154,155,156,157,158,159,160], and two database/registry studies investigated the presence of OA in patients with ATTR amyloidosis [161, 162] (Table 6). The studies which investigated ATTR amyloidosis in OA explored either the prevalence of amyloid or TTR deposits in patients with OA. In three publications, the presence of amyloid deposits led to a diagnosis of ATTR amyloidosis [157, 158, 160]. For those studies which investigated ATTR amyloidosis in OA, the association between OA and ATTR amyloidosis was confirmed through the staining of biopsy samples taken from the knee and/or hip with Congo red, a standard method used to identify amyloid [153,154,155,156,157,158,159,160]. In patients biopsied during total hip arthroplasty (THA), the prevalence of amyloid deposits in the synovial membrane was 22.0%, leading to a diagnosis of ATTRwt amyloidosis in these patients [157]. In patients biopsied during total knee arthroplasty (TKA), the prevalence of amyloid deposits ranged from 8.1 to 33.0% [158, 159]. In an autopsy study by Akasaki et al., TTR amyloid deposits were present in the knee cartilage and synovial fluid in all 12 autopsies of individuals with OA; no analyses of whether systemic ATTR amyloidosis was present were conducted [153,154,155]. With respect to the database/registry studies which reported OA in patients with ATTR amyloidosis, the study by Paccagnella et al., reported on 29 patients with ATTR amyloidosis, finding 59% having had THA and 41% having had TKA [161]. The second study by Ruben et al., reported on 156 patients with unspecified ATTR amyloidosis with CM, finding 12.8% having had THA and 14.1% having had TKA [162].

What is the temporal association between MSK manifestation onset and ATTR amyloidosis diagnosis?

The publications reporting on the temporal association between MSK manifestation onset and a diagnosis of ATTR amyloidosis were limited to CTS, SS, and OA (Fig. 3; Table 8).

Across all CTS-focused publications, CTS symptom onset preceded a diagnosis of ATTR amyloidosis (ATTRv and ATTRwt inclusive) by up to 12 years [21, 23, 44, 47, 49, 57, 96, 105, 109, 134]. In publications reporting on ATTRv amyloidosis separately, the time between CTS symptom onset and diagnosis of ATTRv ranged from 2 to 12 years [21, 44, 47, 49, 134]. This range was 1.3 to 1.9 years in publications reporting on ATTRwt amyloidosis separately [57, 96].

Three studies investigated the temporal association between SS and ATTR amyloidosis; one reported SS symptom onset preceding a diagnosis of ATTRv amyloidosis by approximately 2 years [178], while another reported a 7.4 years delay before an ATTRwt amyloidosis diagnosis [140]. In the same cohort of patients with ATTRwt amyloidosis, CTS symptom onset occurred even earlier than SS symptom onset, preceding the diagnosis of ATTR amyloidosis by 9.5 years [140].

A single publication reported on the temporal association for OA, reporting an average of 7.6 years delay before an ATTR amyloidosis with CM diagnosis was made from OA related surgeries, TKA, and THA [162].

Discussion

Background and rationale

The ability to diagnose ATTR amyloidosis early in the disease course is critical to improving patient prognosis, and MSK manifestations may act as an early indicator of ATTR amyloidosis. This systematic review was conducted to investigate the association between ATTR amyloidosis and MSK manifestations, and to investigate the temporal association between MSK manifestation onset and ATTR amyloidosis diagnosis, in order to potentially aid clinicians in identifying and diagnosing the disease earlier. MSK manifestations, including CTS, SS, OA, among others, were found to be associated with a diagnosis of ATTR amyloidosis (Tables 2, 3, 4, 5, 6 and 7). These manifestations were reported to precede the diagnosis of ATTR amyloidosis by years and could be one of the earliest signs of the disease (Table 8). One of the major systemic manifestations of ATTR amyloidosis is CM which causes progressive heart failure, that can lead to significant morbidity and mortality [3, 10]. The number of patients with ATTRv amyloidosis with cardiomyopathy is estimated to be approximately 40,000 to 50,000 globally [10]. Although the exact prevalence of ATTRwt is not known, it is significantly more common than ATTRv, and CM is the most frequent and predominant systemic involvement in ATTRwt amyloidosis [3, 10]. Awareness of and timely detection of MSK manifestations, months or, even years ahead of the beginning of CM can lead to a significant improvement in the care of these patients [180,181,182].

Limitations

This systematic review is not all-encompassing, and caution should be exercised when drawing conclusions from such a heterogenous evidence base, including many studies reporting on a small number of patients. With the use of machine learning harnessing big data from registries and electronic health records and advanced statistical methodologies, it may be possible to enhance our understanding of the association between MSK manifestations and ATTR amyloidosis. For example, with the application of machine learning, Willis et al. determined which patients with heart failure were ‘at risk’ for developing ATTR amyloidosis; CTS and OA were highlighted as clinical predictive indicators of interest [172]. The potential benefit of utilizing MSK manifestations associated with ATTR amyloidosis to reduce the delay in diagnosis supports further research in the field.

The included publications were highly heterogenous in terms of how the possible association of ATTR amyloidosis with MSK manifestations was demonstrated (Tables 2, 3, 4, 5, 6 and 7). Biopsy followed by tissue staining of MSK or other specified tissues [14, 16, 18, 21, 22, 25, 27, 30, 33,34,35,36,37, 44, 51, 61, 63, 66, 68, 74, 75, 81, 91, 92, 94,95,96, 99, 101, 102, 104, 106,107,108,109,110,111,112,113,114,115, 117,118,119, 121, 124,125,126,127,128,129,130,131, 134, 139, 148,149,150, 152,153,154,155,156,157,158,159,160, 171, 173, 175, 177, 183] were common. However, detecting amyloid in MSK tissues alone does not necessarily mean a patient is or will be diagnosed with ATTR amyloidosis. Tc-99 m PYP/DPD scintigraphy [19, 20, 24, 29, 37, 39, 41, 42, 45, 51, 58, 60, 63, 64, 66, 68, 69, 73, 77, 78, 80, 95, 96, 109, 110, 118, 120, 122, 132, 137,138,139, 148, 152, 165, 166], a non-invasive diagnostic method which has been more commonly used during last several years to make a diagnosis of cardiac amyloidosis [3], was also used to confirm the disease in 30% of the publications included in this review (Table 2). Additionally, methods such as mass spectrometry were utilized to confirm that amyloid was caused by TTR [14, 16, 18, 108, 112, 114, 115, 131, 149, 152, 165]. Another significant limitation is that, although an association between MSK manifestations and ATTR amyloidosis is shown in the literature, it does not necessarily demonstrate causation in all cases. Some MSK manifestations seen in patients with (or who will be diagnosed in the future with) ATTR amyloidosis may not be caused by early amyloid deposition. It will be necessary for clinicians and future researchers to take these limitations into account.

What evidence supports the association between ATTR amyloidosis and MSK manifestations?

The current evidence supports that many MSK manifestations are associated with a diagnosis of ATTR amyloidosis. The MSK manifestation most commonly associated with ATTR amyloidosis is CTS; however, SS, OA, BTR, RCI, TF, among others, were also identified. The exact prevalence of CTS in patients with ATTR amyloidosis remains unclear, with both CTS and ATTR amyloidosis prevalence estimates reported bi-directionally having a broad range. Similarly, no clear trend was identified regarding whether the association with CTS is stronger (indicated by a higher prevalence) in patients with ATTRv or ATTRwt amyloidosis. Nonetheless, given the extent of the identified literature reporting a possible association between CTS and ATTR amyloidosis, patients with CTS may represent a population where targeted screening for ATTR amyloidosis would be valuable [184].

SS was also often associated with ATTR amyloidosis, with similar prevalence estimates identified in patients with ATTRv and ATTRwt amyloidoses. Notably, where the prevalence of CTS and SS was explored in the same patient cohorts with ATTRv or ATTRwt amyloidosis, CTS was more prevalent than SS in all reports [134,135,136, 139, 143, 147].

Finally, the identified evidence supports that ATTR amyloidosis may be prevalent in patients who previously underwent surgery (THA and/or TKA) for OA. TTR amyloid has been detected in the tissues from the joints of patients with OA, which may or may not be indicative of a diagnosis of ATTR amyloidosis, which was confirmed only in three publications. An interesting case series by Akasaki et al., found that all 12 OA patients who donated their knee articular cartilage for biopsy at autopsy had amyloid deposits in their tissue samples [153,154,155]. Although further research is needed, the findings of this publication suggest that there may be value for surgeons to consider biopsy and staining with Congo red in patients who undergo knee or hip surgery for OA.

What is the temporal association between MSK manifestation symptom onset and ATTR amyloidosis diagnosis?

The current evidence highlights that CTS and SS symptom onset can occur months to years, or even decades, before the diagnosis of ATTR amyloidosis [21, 23, 44, 47, 49, 57, 96, 105, 109, 134, 140, 162, 178].

The exact length of time that MSK manifestations precede a diagnosis of ATTR amyloidosis is unclear, with great variation reported across publications. However, the current evidence offers insight into how the temporal association between CTS symptom onset and a diagnosis of ATTR amyloidosis might differ between patients with ATTRv and ATTRwt amyloidosis. According to the current review, CTS symptom onset appears to precede a diagnosis of ATTRv amyloidosis by a substantially longer period than a diagnosis of ATTRwt amyloidosis [21, 44, 47, 49, 96, 134].

Care needs to be taken in the interpretation of the results from these studies given the variation in methodology. For example, at the time of MSK surgery, TTR amyloid deposition may not have occurred within the tissue taken for biopsy, which may confound clinical diagnosis in these patients [153, 160, 175]. Currently, there is no clear order to ATTR amyloid deposition within MSK tissues, i.e., no specific tissue has been identified as the ‘gold standard’ for early detection of ATTR amyloidosis, and biopsy results can vary according to tissue type [153, 160, 175].

Conclusion

Increased awareness of the MSK manifestations associated with ATTR amyloidosis can enable earlier diagnosis and improve outcomes, given there are effective treatments for this rapidly progressive and fatal condition. Surgeons can play a critical role in early diagnosis of ATTR amyloidosis by recognizing associated MSK manifestations. Currently available data, summarized in this first systematic review conducted on the association between MSK manifestations and ATTR amyloidosis, demonstrates that MSK manifestations can be one of the earliest signs of ATTR amyloidosis; however, it should be kept in mind that the available data is heterogenous, and the extent of the causal relationship between MSK manifestations and ATTR amyloidosis should be further investigated.

Availability of data and materials

All data from the review are available within the references included in this manuscript. Only peer-reviewed data reported in published articles, and data presented at congresses and subsequently published as abstracts were used.

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Acknowledgements

The authors would like to thank and acknowledge Louise Heron, Patrick Lavelle, and Fleur Howells from Adelphi Values PROVE™ for their support in conducting the literature review and drafting content.

Funding

This systematic review was funded by Alnylam Pharmaceuticals.

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Authors and Affiliations

  1. Alnylam Pharmaceuticals, Cambridge, MA, US

    Emre Aldinc & Catherine Summers

  2. Baylor Scott & White Heart and Vascular Hospital, Dallas, TX, US

    Courtney Campbell

  3. Rigshopsitalet, University of Copenhagen, Copenhagen, Denmark

    Finn Gustafsson

  4. Adelphi Values PROVE™, Bollington, UK

    Abigail Beveridge, Richard Macey & Laura Marr

  5. Brigham and Women’s Hospital, Boston, MA, US

    Dafang Zhang

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Contributions

Catherine Summers and Emre Aldinc provided conceptualization and review of the protocol, results, and interpretation. Dr Courtney Campbell, Dr Finn Gustafsson, and Dr Dafang Zhang provided expert guidance including conceptualization and review of the protocol, results, and interpretation. Richard Macey, Abigail Beveridge, and Laura Marr conducted the review of the literature, developed the protocol, and drafted the manuscript. All authors were involved in the review process and approval of the manuscript content.

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Correspondence to Emre Aldinc.

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Competing interests

Catherine Summers and Emre Aldinc are employees of Alnylam Pharmaceuticals. Finn Gustafsson is an adviser to Alnylam, Ionis and Pfizer. Courtney Campbell is an adviser to Alnylam and Pfizer and has received research support from Alnylam and Akari Therapeutics. Richard Macey, Abigail Beveridge, and Laura Marr are employees of Adelphi Values PROVE™. Adelphi Values PROVE™ received funding from Alnylam Pharmaceuticals for the conduct of the review, from development of the systematic review methodology through to overseeing the final formatting and manuscript submission processes.

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Supplementary Information

Additional file 1: Supplement 1.

PICOTS criteria for study inclusion and exclusion in the SLR. Supplement 2. Ovid® search strategies for EMBASE and Medline (run on November 3rd, 2021). Supplement 3. Case studies excluded from the systematic literature with ATTR MSK manifestation

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Aldinc, E., Campbell, C., Gustafsson, F. et al. Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review. BMC Musculoskelet Disord 24, 751 (2023). https://doi.org/10.1186/s12891-023-06853-5

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BMC Musculoskeletal Disorders

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