**Abstract**

In this chapter, the authors will discuss the epidemiology and clinical presentations of amyloidosis. The main body of this chapter will concentrate on treatment options, both FDA-approved and experimental, specific to the various forms of amyloidosis. Since this set of diseases can affect multiple organ systems, we tackle the therapeutic avenues and the current challenges in each system under clinical investigation, including neurological, psychiatric, gastrointestinal, cardiovascular, endocrine, renal and hematologic, in addition to options for palliative treatment for severe symptom management and improved quality of life. Several recent groundbreaking discoveries have opened up the potential for successful treatment of peripheral and central neurological amyloidoses making this an exciting and evolving field.

**Keywords:** transthyretin, antisense oligonucleotide, protein aggregation

## **1. Epidemiology**

Amyloidosis is a rare, albeit likely underdiagnosed, disorder [1]. Claims data in the United States shows prevalence of amyloid light-chain (AL) amyloidosis increased between 2007 and 2015 from 15.5 to 45 cases per million [2]. Incidence did not significantly increase over this time period, but ranged from 9.7 to 14 cases per million-person years [2]. This equates to more than 12,000 people in the US currently living with this disorder. Older data, from 1950 to 1989, found 9 cases per million people, more evidence of an increasing prevalence over time [3]. The trend in age- and sex-adjusted incidence rate of amyloidosis per million person years from 1950 to 1989 was not found to be significant (**Figure 1**).

This phenomenon could be explained by increased detection and diagnosis. Studies in the United Kingdom and Sweden demonstrated a prevalence of 20 cases per million and incidence of 5 cases per million-person years, 3 of them being AL, and 1 amyloid A (AA) amyloidosis [1, 4]. A US study found a mean age at diagnosis of AL amyloidosis of 63 with a standard deviation of 12, 55% male [2]. International studies also show that men are slightly more likely to be diagnosed with AL, however, AA amyloidosis more commonly affects women, possibly due to higher prevalence of underlying rheumatoid arthritis [1].

#### **Figure 1.**

*Age- and sex-adjusted average annual incidence rates of amyloidosis per million person-years in Olmsted County, Minnesota from 1950 to 1989.*

AL amyloidosis is more prevalent than AA amyloidosis in developed countries, however, in developing countries and some Mediterranean countries, AA is more prevalent (**Figure 2**). Other studies have shown AL to be more prevalent than AA in developed countries, but in developing nations AA has a higher prevalence than AL [1].

This follows the logic of the epidemiologic transition, since as a country develops, diseases transition from infectious to chronic disease states. In developing nations, endemic infections such as tuberculosis or leprosy lead to AA amyloidosis,

**23**

**2.1 Pain**

**2.2 Depression**

*Amyloidosis: Systems-Based Therapies*

*DOI: http://dx.doi.org/10.5772/intechopen.85201*

subtypes from 21% in 1977 to 44% in 2013 [5].

survival time ranging from 6 months to 4 years [1].

sequelae of amyloidosis have been well researched [8].

to clinical dementia due to their anticholinergic effects.

**2. Palliative treatments for amyloidosis**

while in developed nations chronic diseases lead to AL amyloidosis. The exception to this is Mediterranean nations, while developed, have a higher prevalence of AA amyloidosis. This is likely due to relatively high prevalence autoinflammatory diseases such as familial Mediterranean fever. For example, in Spain, AL amyloidosis has become the most prevalent subtype, increasing in frequency relative to other

The prognosis for amyloidosis varies by subtype, treatment modality, extent of cardiac involvement and, to a lesser degree, hepatic and autonomic involvement [1]. A Swedish study estimated median survival to be 3, 4, and 6 years for AL, AA, and localized amyloidosis [6]. In regards to systemic amyloidosis, a median survival time of 32 months was seen in the UK [4]. Older studies found untreated median

The protein deposition and accumulation inherent in amyloidosis causes a wide range of systemic symptoms, and patients may also suffer from side effects of curative therapies. Though many mistakenly believe palliative interventions are only for end of life care, palliative treatments can be implemented at any stage of illness, and may help curb severe symptoms. In many forms of cancer, early palliative interventions have been shown to increase quality of life for both patients and caregivers [7]. While no studies have been conducted to evaluate the effectiveness of palliative therapies on amyloidosis specifically, palliative treatments for many of the common

Neuropathic pain (NP) is the most common pain sensation reported in people with amyloidosis. NP is notoriously difficult to control, and is often not responsive to typical pain regimens. Antidepressants, anticonvulsants, opioids, and topical medications are the most common pharmacologic agents used. Unfortunately, many of these agents have their own side effects, and should be used with caution [8].

There has long been a link noted between depression and dementia, and depression has been viewed as both a prodrome and a risk factor for dementia. About half of patients with late-onset depression are found to have cognitive impairment, and the prevalence of dementia in depression has been reported between 9 and 68% [9]. A past history of depression is a known risk factor for developing Alzheimer's disease and vascular dementia, even when the episode of depression occurred over 10 years prior. Rather than a prodrome, depression seems to be a risk factor for Alzheimer's disease, as evidenced by a neuropathological study showing increased neurofibrillary tangles and plaques in the hippocampus in those with a history of depression [10]. Depression is linked to hypercortisolemia, which may cause prolonged damage to the hippocampus. Depression may also be a psychological reaction to the diagnosis of cognitive impairment, and may even reveal previously clinically silent cognitive impairment by depleting cognitive reserve [11]. Additionally, the use of tricyclic antidepressants in the elderly may also contribute

The link between depression and Alzheimer disease may involve mechanisms in the metabolism of β-amyloid peptides in the brain. A recent study has shown

**Figure 2.** *Mortality of amyloidosis subtypes UK from 2000 to 2020,008 (n = 903).*

*Amyloidosis: Systems-Based Therapies DOI: http://dx.doi.org/10.5772/intechopen.85201*

while in developed nations chronic diseases lead to AL amyloidosis. The exception to this is Mediterranean nations, while developed, have a higher prevalence of AA amyloidosis. This is likely due to relatively high prevalence autoinflammatory diseases such as familial Mediterranean fever. For example, in Spain, AL amyloidosis has become the most prevalent subtype, increasing in frequency relative to other subtypes from 21% in 1977 to 44% in 2013 [5].

The prognosis for amyloidosis varies by subtype, treatment modality, extent of cardiac involvement and, to a lesser degree, hepatic and autonomic involvement [1]. A Swedish study estimated median survival to be 3, 4, and 6 years for AL, AA, and localized amyloidosis [6]. In regards to systemic amyloidosis, a median survival time of 32 months was seen in the UK [4]. Older studies found untreated median survival time ranging from 6 months to 4 years [1].

## **2. Palliative treatments for amyloidosis**

The protein deposition and accumulation inherent in amyloidosis causes a wide range of systemic symptoms, and patients may also suffer from side effects of curative therapies. Though many mistakenly believe palliative interventions are only for end of life care, palliative treatments can be implemented at any stage of illness, and may help curb severe symptoms. In many forms of cancer, early palliative interventions have been shown to increase quality of life for both patients and caregivers [7]. While no studies have been conducted to evaluate the effectiveness of palliative therapies on amyloidosis specifically, palliative treatments for many of the common sequelae of amyloidosis have been well researched [8].

#### **2.1 Pain**

*Amyloid Diseases*

**Figure 1.**

*County, Minnesota from 1950 to 1989.*

AL amyloidosis is more prevalent than AA amyloidosis in developed countries, however, in developing countries and some Mediterranean countries, AA is more prevalent (**Figure 2**). Other studies have shown AL to be more prevalent than AA in developed countries, but in developing nations AA has a higher prevalence than AL [1]. This follows the logic of the epidemiologic transition, since as a country develops, diseases transition from infectious to chronic disease states. In developing nations, endemic infections such as tuberculosis or leprosy lead to AA amyloidosis,

*Age- and sex-adjusted average annual incidence rates of amyloidosis per million person-years in Olmsted* 

**22**

**Figure 2.**

*Mortality of amyloidosis subtypes UK from 2000 to 2020,008 (n = 903).*

Neuropathic pain (NP) is the most common pain sensation reported in people with amyloidosis. NP is notoriously difficult to control, and is often not responsive to typical pain regimens. Antidepressants, anticonvulsants, opioids, and topical medications are the most common pharmacologic agents used. Unfortunately, many of these agents have their own side effects, and should be used with caution [8].

#### **2.2 Depression**

There has long been a link noted between depression and dementia, and depression has been viewed as both a prodrome and a risk factor for dementia. About half of patients with late-onset depression are found to have cognitive impairment, and the prevalence of dementia in depression has been reported between 9 and 68% [9]. A past history of depression is a known risk factor for developing Alzheimer's disease and vascular dementia, even when the episode of depression occurred over 10 years prior. Rather than a prodrome, depression seems to be a risk factor for Alzheimer's disease, as evidenced by a neuropathological study showing increased neurofibrillary tangles and plaques in the hippocampus in those with a history of depression [10]. Depression is linked to hypercortisolemia, which may cause prolonged damage to the hippocampus. Depression may also be a psychological reaction to the diagnosis of cognitive impairment, and may even reveal previously clinically silent cognitive impairment by depleting cognitive reserve [11]. Additionally, the use of tricyclic antidepressants in the elderly may also contribute to clinical dementia due to their anticholinergic effects.

The link between depression and Alzheimer disease may involve mechanisms in the metabolism of β-amyloid peptides in the brain. A recent study has shown

significant associations between geriatric depression and β-amyloid peptide deposits in the insula, hippocampus, and amygdale [12]. Another recent study showed the link between hereditary gelsolin amyloidosis (AGel) and neuropsychiatric changes. The gelsolin mutation is associated with cerebrovascular fragility, and is an autosomal dominant form of systemic amyloidosis. The study found visuoconstructional difficulties in the AGel group in both the block design and drawing tasks. While overall processing speed was similar in both groups, the AGel group produced more errors [13]. The behavioral and psychological symptoms of people with dementia result in greater cognitive and functional impairment, and are associated with greater amyloid deposition in the neurodegenerative process leading to Alzheimer's disease [14].
