Supplementary Figure 1.

Supplementary Figure 1. Lifetime prevalence of carpal tunnel syndrome at the time of cardiac

assessment, stratified by gender, amyloidosis aetiology and presence of cardiac involvement. The

dashed lines represent the lifetime prevalence at reference age (i.e. median age within each aetiology)

in the general population.

AL, amyloid light-chain; ATTR, transthyretin-related amyloidosis; ATTRm hereditary transthyretin-related amyloidosis; ATTRwt, wild-type transthyretin-related amyloidosis.

Supp

All ATTR

Person-years 20,313 14,924 5,389

Observed cases 52 47 5

Expected cases 13.79^a 9.80^a 3.99^a

SIR (95%CI) 3.77 (2.82–4.94) 4.80 (3.52–6.38) 1.25 (0.41–2.92) ATTRm

Person-years 12,242 6,853 5,389

Observed cases 25 20 5

Expected cases 8.06^a 4.07^a 3.99^a

SIR (95%CI) 3.10 (2.01–4.58) 4.92 (3.00–7.59) 1.25 (0.41–2.92) ATTRwt

Person-years 8,070^c 8,070^c /

Observed cases 27 27 /

Expected cases 5.73^a 5.73^a /

SIR (95%CI) 4.71 (3.10–6.85) 4.71 (3.10–6.85) /

Abbreviations: ATTR, transthyretin-related amyloidosis; ATTRm hereditary transthyretin-related amyloidosis; ATTRwt, wild-type transthyretin-related amyloidosis; CI, confidence interval; SIR, standardized incidence ratio.

aExpected counts based on Mattioli et al (2008).

Supplementary Table 2. Age (5-year classes) standardized incidence ratios of carpal tunnel syndrome surgery by gender, presence of cardiac involvement, and amyloidosis aetiology (ATTRm and ATTRwt).

Females Males

Cardiac involvement Cardiac involvement

Aetiology All patients Present Absent All patients Present Absent

All ATTR

Person-years 6,215 3,261 2,953 14,098 11,662 2,436

Observed cases 13 8 5 39 39 0

Expected cases 8.29^a 4.93^a 3.36^a 5.50^a 4.87^a 0.63^a

SIR (95%CI) 1.57 (0.83–2.68) 1.62 (0.70–3.20) 1.49 (0.48–3.47) 7.09 (5.04–9.69) 8.01 (5.69–10.9) 0.00 (0.00–5.82) ATTRm

Person-years 4,858 1,905 2,953 7,384 4,948 2,436

Observed cases 9 4 5 16 16 0

Expected cases 5.85^a 2.49^a 3.36^a 2.21^a 1.58^a 0.63^a

SIR (95%CI) 1.54 (0.70–2.92) 1.61 (0.44–4.12) 1.49 (0.48–3.47) 7.23 (4.13–11.7) 10.1 (5.79–16.4) 0.00 (0.00–5.82) ATTRwt

Person-years 1,356 1,356 / 6,714 6,714 /

Observed cases 4 4 / 23 23 /

Expected cases 2.44^a 2.44^a / 3.29^a 3.29^a /

SIR (95%CI) 1.64 (0.45–4.19) 1.64 (0.45–4.19) / 6.99 (4.43–10.5) 6.99 (4.43–10.5) /

Abbreviations: ATTR, transthyretin-related amyloidosis; ATTRm hereditary transthyretin-related amyloidosis; ATTRwt, wild-type transthyretin-related amyloidosis;

CI, confidence interval; SIR, standardized incidence ratio.

aExpected counts based on Mattioli et al (2008).

Supplementary Table 3. Age (5-year classes) standardized incidence ratios of carpal tunnel syndrome by amyloidosis aetiology, gender, and broad age class.

Aetiology Sex Age (years) Pyrs Obs Exp^a SIR (95% CI)

ATTRm Females <60 4642 8 5.30 1.51 (0.65–2.97)

ATTRm Females 60-69 164 1 0.42 2.37 (0.06–13.22)

ATTRm Females 70-79 47 0 0.11 0.00 (0.00–32.15)

ATTRm Females ≥80 6 0 0.01 0.00 (0.00–494.13)

ATTRm Males <60 6934 11 1.72 6.41 (3.20–11.47)

ATTRm Males 60-69 338 3 0.34 8.91 (1.84–26.05)

ATTRm Males 70-79 104 2 0.15 13.08 (1.58–47.27)

ATTRm Males ≥80 8 0 0.01 0.00 (0.00–458.02)

ATTRwt Females <60 1020 0 1.66 0.00 (0.00–2.23)

ATTRwt Females 60-69 157 2 0.4 4.97 (0.60–17.94)

ATTRwt Females 70-79 131 2 0.32 6.23 (0.75–22.52)

ATTRwt Females ≥80 48 0 0.06 0.00 (0.00–58.49)

ATTRwt Males <60 5377 2 1.71 1.17 (0.14–4.23)

ATTRwt Males 60-69 776 9 0.79 11.37 (5.20–21.58)

ATTRwt Males 70-79 481 11 0.71 15.59 (7.78–27.9)

ATTRwt Males ≥80 81 1 0.09 11.69 (0.30–65.15)

Abbreviations: ATTR, transthyretin-related amyloidosis; ATTRm hereditary transthyretin-related amyloidosis; ATTRwt, wild-type transthyretin-related amyloidosis; CI, confidence interval; Exp, expected cases; Obs, observed cases; pyrs, person-years; SIR, standardized incidence ratio.

aExpected counts based on Mattioli et al (2008).

Supplementary Table 4. Standardized incidence ratios of carpal tunnel syndrome surgery by amyloidosis aetiology, sex, and time before the diagnosis of amyloidosis.

Aetiology Sex Time before the diagnosis of

amyloidosis Pyrs Obs Exp^a SIR^a (95%CI)

ATTRm Both ≥10 years 7,529 7 3.64 1.93 (0.77–3.97)

Both 5 to 9 years 776 8 1.06 7.51 (3.24–14.8)

Both <5 years 990 8 1.43 5.60 (2.42–11.0)

Females ≥10 years 2,421 1 2.43 0.41 (0.01–2.29)

Females 5 to 9 years 269 3 0.73 4.13 (0.85–12.1)

Females <5 years 365 3 0.96 3.13 (0.65–9.15)

Males ≥10 years 5,109 6 1.20 4.98 (1.83–10.9)

Males 5 to 9 years 507 5 0.34 14.8 (4.80–34.5)

Males <5 years 625 5 0.47 10.6 (3.45–24.8)

ATTRwt Both ≥10 years 7,220 11 4.55 2.42 (1.21–4.33)

Both 5 to 9 years 444 11 0.63 17.4 (5.99–15.1)

Both <5 years 407 5 0.56 8.97 (2.62–8.04)

Females ≥10 years 1,214 2 2.15 0.93 (0.11–3.37)

Females 5 to 9 years 74 1 0.17 5.84 (0.15–32.6)

Females <5 years 69 1 0.13 7.93 (0.20–44.2)

Males ≥10 years 6,006 9 2.40 3.75 (1.71–7.12)

Males 5 to 9 years 370 10 0.46 21.7 (10.4–40.0)

Males <5 years 339 4 0.43 9.28 (2.53–23.7)

Abbreviations: ATTR, inherited transthyretin-related amyloidosis; ATTRm, inherited transthyretin-related amyloidosis;

ATTRm, acquired transthyretin-related amyloidosis; CI, confidence interval; Exp, expected cases; Obs, observed cases;

pyrs, person-years; SIR, standardized incidence ratio.

aSIR based on rates reported by Mattioli et al (2008).

Supplementary Table 5. Hazard ratio of cardiac involvement after carpal tunnel syndrome. Estimates from Cox proportional hazards regression models with age as the main temporal axis.

A^LL ATTR ^PATIENTS

Crude estimates Estimates adjusted by sex

CTS surgery^a Cases with cardiac involvement HR (95% CI) P HR (95% CI) P

No 185 1.00 (Ref.) 1.00 (Ref.)

Yes 47 2.28 (1.62–3.22) <0.001 2.24 (1.58–3.16) <0.001

ATTR^MPATIENTS

Crude estimates Estimates adjusted by sex

CTS surgery^a Cases with cardiac involvement HR (95% CI) P HR (95% CI) P

No 105 1.00 (Ref.) 1.00 (Ref.)

Yes 20 3.01 (1.82–4.97) <0.001 2.90 (1.75–4.81) <0.001

ATTRWTPATIENTS

Crude estimates Estimates adjusted by sex

CTS surgery^a Cases with cardiac involvement HR (95% CI) P HR (95% CI) P

No 80 1.00 (Ref.) 1.00 (Ref.)

Yes 27 1.72 (1.09–2.70) 0.019 1.61 (1.02–2.53) 0.041

Abbreviations: ATTRm, inherited transthyretin-related amyloidosis; ATTRm, acquired transthyretin-related amyloidosis; CI, confidence interval; CTS, carpal tunnel syndrome; HR, hazard ratio; Ref., reference category.

a CTS surgery modelled as a time-varying covariate.

Supplementary Figure 2. Risk of cardiac involvement after carpal tunnel syndrome (time-varying covariate) among patients with

acquired transthyretin-related amyloidosis. Analysis stratified by mutation. Cumulative hazard functions (Nelson-Aalen estimator) and

hazard ratios from Cox proportional hazards regression models.

CTS, carpal tunnel syndrome; HR, hazard ratio.

Supplementary table 6. Hazard ratio of death. Estimates from univariable Cox proportional hazard regression models.

All patients ATTRm patients ATTRwt patients

Characteristics HR (95%CI) P HR (95%CI) P HR (95%CI) P

CTS surgery

No 1.00 (Ref.) 1.00 (Ref.) 1.00 (Ref.)

Yes 2.26 (1.12–4.58) 0.023 1.74 (0.57–5.28) 0.327 2.43 (0.95–6.20) 0.063

Gender

Females 1.00 (Ref.) 1.00 (Ref.) 1.00 (Ref.)

Males 2.19 (0.97–4.93) 0.059 2.16 (0.80–5.88) 0.131 1.05 (0.24–4.52) 0.953 Age, (years) 1.05 (1.03–1.08) <0.001 1.07 (1.03–1.11) <0.001 1.05 (0.99–1.12) 0.137 Aetiology of amyloidosis

ATTRm 1.00 (Ref.) NA NA NA NA NA NA

ATTRwt 2.21 (1.20–4.06) 0.011 NA NA NA NA NA NA

Mutation (ATTRm only)

Glu89Gln NA NA NA 1.50 (0.40–5.59) 0.547 NA NA NA

Ile68Leu NA NA NA 1.58 (0.46–5.45) 0.465 NA NA NA

Val30Met NA NA NA 1.00 (Ref.) NA NA NA

Others NA NA NA 0.90 (0.25–3.19) 0.871 NA NA NA

Cardiac involvement

No 1.00 (Ref.) 1.00 (Ref.) NA NA NA

Yes 2.01 (0.84–4.77) 0.115 1.48 (0.58–3.78) 0.416 NA NA NA

Mean wall thickness, [mm] 1.07 (0.99–1.15) 0.097 1.07 (0.96–1.19) 0.206 0.97 (0.84–1.12) 0.682 Left atrial diameter, [mm] 1.05 (1.01–1.09) 0.009 1.10 (1.04–1.16) 0.001 0.98 (0.94–1.03) 0.377 LVEF, [%] 0.98 (0.96–1.00) 0.025 0.96 (0.93–0.99) 0.016 1.00 (0.97–1.04) 0.729 Cardiac valve thickening

Supplemetary table 7. CTS prevalence in patients affected by systemic amyloidosis, according to published data.

Study

All patients

Global CTS prevalence

CTS prevalence in

AL

CTS prevalence in

ATTRm

CTS prevalence in

ATTRwt

CA prevalenc

e 1 aus dem Siepen et al, Clin Res

Cardiol, 2018⁶

389 pts 77 carriers

58%

13%

- -

57% 60%

-

100%

0%

2 Gagliardi et al, Eur J Heart Fail,

2018¹⁹ 149 40% - 43%

(Ile68Leu)

37% 98%

3 Gonzalez-Lopez et al, Eur Heart

J, 2017⁷ 108 33% - - 33% 100%

4 Rubin et al, Amyloid, 2017⁹

313 36% 11% 59% 52% 100%

5 Maurer et al, JACC, 2016⁸

178 32% - 29%

(Val122Ile)

33% 84%

6 Damy et al, Amyloid, 2016²⁰

198 31% 16% 49% 48% 83%

7 Connors et al, Circulation, 2016²¹

121 46% - - 46% 98%

8 Nakagawa et al, Amyloid, 2016²⁴ 31 58% - - 58% -

11 Lefaucheur et al, J Neurol, 2013²³

20 15% - 15% - /

12 Rapezzi et al, Eur Heart J, 2013¹⁸

186 35% - 35% - 75%

13 Rapezzi et al, Circulation, 2009⁵

233 20% 13% 38% 13% 100%

Supplemetary table 8. Prevalence and type of amyloid deposits in tenosinovial tissue of patients undergoing carpal tunnel surgery.

Study

All patients Histological diagnosis Mean age Male/Femal e (male %)

1 Sperry et al, JACC, 2018¹¹ 98 10% amyloid:

7% ATTR 2% AL 1% unknown

68 (61-74) 51:47 (52%)

2 Sekijima et al, Hum Pathol, 2011² 100 34% ATTR 67·3 ± 12·1 26:74

5 Stein et al,

Virchows Arch A Pathol Anat Histopathol, 1987²⁷

108 19% amyloid:

15% ATTR 1 % AL 3% AA

- -