demographic and pathological characteristics
There were 876 patients who fulfilled the inclusion criteria in the study, of whom 9 had a record of non-AL amyloidosis in the Catastrophic Disease Database, and 26 patients switched to another ICD amyloidosis code during the study period (Figure 1). After applying the exclusion criteria, there were 841 patients with newly diagnosed AL amyloidosis between 2016 and 2019, of whom 58.74% (494/841) were men (Table S1). The mean age was 61.4 years (standard deviation [SD] 14.09, 11–94 years), and 81.1% of patients were 50 years of age or older at the time of diagnosis. More than half of patients (51.6%) had CCI scores of 2. The most common comorbidities were malignancy (21.9%), peptic ulcer disease (19.5%), kidney disease (19.4%), and diabetes without chronic complications (19.1%) (Table S2). Cardiac-related comorbidities were present in 28.54% of patients, of whom 20.69% had heart failure, 10.58% had conduction disorder, and 4.76% had cardiomyopathy. Renal-related comorbidities were present in 23.19% of patients and included chronic kidney disease (14.15%). Liver-related diseases were present in 2.14% of patients (Table 1). Of the 240 patients with co-morbid heart disease, 15 (6.25%) were aged 20-49 years and 51 (21.25%) were 50-59 years old. 73% of patients with heart disease are aged 60 years and over (Table S2). Demographic and pathological features were similar in patients enrolled across each calendar year (Table S1).
There is no specific code for AL amyloidosis in either the ICD-9 or ICD-10. To assess the robustness of our diagnostic criteria, we evaluated the proportion of patients included in the study who received at least one treatment for AL amyloidosis (chemotherapy, proteasome inhibitor, immunomodulating factor, radiotherapy, steroids, autologous stem cell transplantation) during the follow-up period. There were 66.6% of patients who received at least one treatment. However, no treatment can be determined in patients with mild disease13, and new agents such as bortezomib were not reimbursed by the Taiwanese NHI at the time of the study, and therefore were not registered with the NHIRD if prescribed. Therefore, treatment history could not be used to confirm a diagnosis of AL amyloidosis in our group.
We secondly assessed the robustness of our diagnostic criteria by evaluating the demographics, disease features, and case mortality among 4442 patients who did not undergo confirmatory biopsy after receiving the initial diagnosis of AL amyloidosis (Table 1). Compared with patients who underwent biopsy, patients diagnosed with AL amyloidosis who did not undergo biopsy were younger (median 61.4 years vs 56.4, s<0.0001), had significantly lower morbidities (median CCI scores 0.82 vs 2.07, s<0.0001), the incidence was significantly lower than all comorbidities, and a significantly lower proportion died during the follow-up period (5.13% vs 19.74%, s<0.0001). These data indicate that patients with an initial diagnosis of AL amyloidosis who did not undergo confirmation biopsy subsequently received an alternative diagnosis. This is not unexpected given the nonspecific clinical presentation of amyloid disease, which can mimic many other conditions. The results provided some confidence that the criteria for inclusion of the ICD code as well as evidence of biopsy increased the specificity of the diagnosis of AL amyloidosis in the database. However, we cannot exclude that a small portion of the cases without confirmed biopsy were patients with AL amyloidosis who did not undergo biopsy for any reason.
Occurrence and fatality rates
The annual incidence of age-adjusted amyloidosis was 5.73 per million in 2016, 6.55 per million in 2017, 6.08 per million in 2018, and 5.26 per million in 2019 (Fig. 2a). The proportion of all-cause mortality fluctuated from 1.7% in 2016 to 2.9% in 2019 (Fig. 2b).
Effect of age and gender on all-cause mortality
The incidence rates of AL amyloidosis increased with age and were similar in men and women up to the age of 50 years, after which the incidence rates increased significantly more in men than in women (Table 2). While the incidence increased slightly in women after the age of 60 years, it continued to increase in men until the age of 70 years. During the observation period, AL amyloidosis rates ranged from 9.65 to 11.78 per million population in men (all ages) and from 6.36 to 8.18 per million women (all ages).
The all-cause case-fatality rate was similar in men and women and similarly increased from the age of 40 years in men and women (Table 3), and the highest all-cause case-fatality rates, about 10%, were observed in patients aged 80 years and older.
In the Cox ratio regression model, the risk of all-cause mortality was higher in men than in women (HR 1.49.2) [95% CI 1.07–2.09]; s= 0.019) and increases with age. The risk of death was 6.9 times higher in patients over 70 years of age with AL amyloidosis than 18 to 49 years of age with AL amyloidosis (HR 6.9). [95% CI 2.98–15.92]; s<0.0001) (Table 4).
Effect of heart, kidney and liver related comorbidities on all causes of mortality
We assessed the risk of all-cause death in patients with only combined heart and/or renal disease or with joint liver disease against a reference group without any co-morbidities at diagnosis. The risk of death was higher in patients with co-morbidity, and the greater risk of all-cause death was associated with co-morbid liver disease (HR 13.509, 95% CI, 7.491–24.363; s<0.0001), followed by renal disease (HR 2.846, 95% CI 1.815-4.462; s<0.0001), heart disease (HR 2.007, 95% CI 1.299–3.102; s= 0.0017). The survival rate was decreased again among patients with combined heart and kidney disease compared with patients with single organ (heart or kidney) disease (HR 4.009, 95% CI 2.541–6.325; s<0.0001).
Six months after diagnosis, less than 50% of patients with liver-related co-morbidity survived, while patients with cardiac and/or renal morbidity did not reach that threshold after 45 months of follow-up (Figure 3).