In 1838, the term “amyloid” was applied by German botanist Mathias Schleiden to a starch-like substance in plants. In 1854, Rudolf Virchow used the term to refer to some sort of abnormal extracellular material he had seen in the liver at autopsy. Virchow noticed that it reacted with sulfuric acid and iodine the same as starch and hence coined the term ” starch-like ” or ” amyloid “. 

About 70 years later, Divry and coworkers discovered that, using Congo red, amyloid deposits gave apple-green birefringence under polarized light. This property remains today essential for the diagnosis of the condition called amyloidosis. 

In 1959, Cohen and Calkins described a unique non-branching fibrillar structure common to all forms of amyloidosis by electron microscopy. This method is still today the most sensitive for the diagnosis of the disorder. 

The epidemiologic characteristics of amyloidosis are difficult to define accurately because the disorder is often underdiagnosed or misdiagnosed. A 2018 systematic review assessed the diagnosed incidence and prevalence of AL amyloidosis in the United States, Europe, Canada, Brazil, Japan, South Korea, Taiwan, and Russia and estimated that approximately 74,000 cases had been diagnosed within the last 20 years, for a prevalence rate of 51 cases per million. The annual incidence in 2018 was estimated to be as low as 6.7 cases per million in Brazil and as high as 14.3 per million in Japan, with the incidence in the US reported at 9.9 per million. 

 In a comprehensive review of 236 cases of systemic amyloidosis by Kyle and Bayrd, 56% were found to be primary and 26% were related to multiple myeloma. 

Demographics related to Race, Sex, and Age: 

• Race: There is no racial predisposition reported for the development of primary systemic amyloidosis. 
• Sex: There is no marked sexual predilection for primary systemic amyloidosis, although Greipp and Kyle, in their large series of 182 patients with the disease, found a slight male predominance. 
• Age: The primary systemic amyloidosis mostly affects adults, the age of 65 years being the average at which the beginning of the disease was reported. 

Primary systemic amyloidosis is a plasma-cell dyscrasia characterized by overproduction of a monoclonal immunoglobulin protein that results in the formation of amyloid fibrils in the extracellular matrix. These fibrils are composed mainly of Ig L-chain material, immunoglobulin light chain, , that includes light chain fragments and, intact light chains or a combination of the two. This condition results from plasma-cell dyscrasia. Diagnosis requires the demonstrating of amyloid deposits in tissue; the kidneys and heart are the most common sites of deposition. Common features include autonomic and sensory neuropathies. 

Skin involvement occurs in 30-40% of patients with primary systemic amyloidosis, and many develop mucocutaneous signs, often early evidence of an underlying plasma-cell dyscrasia. Common skin signs are petechiae, purpura, and ecchymoses. Oral mucocutaneous changes can manifest as localised rubbery papules, petechiae, and ecchymoses/purpura. Macroglossia occurs in approximately 19%. 

Primary systemic amyloidosis is estimated to account for 7% of nonhematological malignancies, but the involvement of gastric carcinoma in this system is extremely rare. Gastrointestinal hemorrhage combined with pseudoobstruction of the small intestine may suggest that clinicians should have differential diagnoses including gastrointestinal amyloidosis. 

The etiology of primary systemic acidosis involves several key factors and mechanisms: 

1. Plasma-cell dyscrasia: In the most part systemic amyloidosis are caused by plasma-cell dyscrasia, a condition in which atypical plasma cells produce a monoclonal immunoglobulin light chain. The precursor for amyloid fibrils is this abnormal light chain. 
2. Over production of monoclonal light chain: A distinct kind of immunoglobulin light chain (usually fake lambda or kappa) is overproduced more than they are supposed to by the plasma cells. Misfolding of these light chains occurs resulting in their aggregation to form insoluble fibrils. 
3. Formation of amyloid fibril: Deposited misfolded light chains within the extracellular matrix of various tissues and organs form amyloid fibrils. Such fibrils are resistant to proteolysis and accrue over time, leading to organ malfunction. 
4. Genetic factors: Even if primary systemic amyloidosis is not directly inherited, the development of the disease can be influenced by genetic predispositions. Several distinct genetic mutations or variations can impact how proteins fold and break down. 
5. Secondary factors: Chronic inflammation or infections can serve as triggers or contributing factors under certain circumstances. However, it should be noted that these factors do not directly cause primary systemic amyloidosis, but their influence may play a role in the development of this disease. 

Advancements in Therapeutics over the past two decades have substantially improved the prognosis of patients with systemic AL amyloidosis. The median survival of patients, even in most risk groups, now exceeds 4 years with the current regimens, while some report even a median survival beyond 10 years. However, median survival for patients in stage 4 remains poor and is usually only about 6 months. 

Prognosis in patients with AL amyloidosis directly depends on the extent of their disease and their response to therapy. Involvement of the heart occurs in approximately 70% of patients with AL amyloidosis and represents an important predictor for survival. The severity of cardiac involvement can be defined based on the levels of cardiac biomarkers represented in the peripheral circulation, such as troponins I and T, brain natriuretic peptide, and N-terminal pro-brain natriuretic peptide. By the same staging system incorporating these biomarkers, Kumar et al. reported the median and estimated 4-year overall survival rates by stage as follows: 

Stage I: Median survival not reached, 4- year survival rate- 73% 

Stage II: Median survival 62.8 months, 4-year survival rate- 52% 

Stage III: Median survival 16.8 months, 4-year survival rate 31% 

Stage IV: Median survival 5.8 months, 4- year survival rate 10% 

A reduction in levels of cardiac biomarker and improvements in free light chian ratios are associated with better survival outcomes after three to six months of treatment. Lilleness et al. found that cardiac response to treatment as measured by BNP levels before and six months after treatment, provides valuable survival prognostication. The median OS (overall survival) based on cardiac response was as follows: 

1. Cardiac response (BNP decrease of ≥50pg/mL and ≥30%) change in BNP), OS not reached 
2. Cardiac stability (BNP decrease of <50pg/mL and <30%) change in BNP), OS 9.2 years 
3. Cardiac progression (BNP increase of ≥50pg/mL or ≥30%), OS 2.8 years 

Symptoms of PSA (primary systemic acidosis) are often too nonspecific to be helpful in making an accurate diagnosis which can cause delays. The initial signs and symptoms may include: 

1. Edema 
2. Paresthesias 
3. Fatigue 
4. Hoarseness 
5. Weight loss 

Classical signs include: 

1. Hepatomegaly 
2. Edema 
3. Macroglossia 
4. Carpel tunnel syndrome 
5. Mucocutaneous lesions 

Primary systemic amyloidosis most frequently involves clinically apparent mucocutaneous involvement, appreciated in 30-40% of patients. The common skin findings are petechiae and ecchymoses due to cutaneous blood vessel involvement. Waxy papules, nodules, or plaques present as typical lesions on the skin in areas like the eyelids, neck, even inguino-anogenital or retroauricular region. 

Diffuse infiltrates may imitate scleroderma or myxedema. Participation of the scalp may give the appearance of diffuse or patchy alopecia. Dystrophic changes in the nail include crumbling, subungual striation, and brittleness. Macroglossia, a classic feature, is often exposed by elastic, tender, and localized papules. 

Diffuse amyloid deposition in muscles, connective tissue, blood vessel walls, and peripheral nerves can lead to myocardial insufficiency, the most frequent cause of death in this incurable disease. Cardiac infiltration may cause angina, infarction, arrhythmias or orthostatic hypotension. Blood vessel infiltration may lead to claudication of the jaw or legs. Renal amyloidosis usually presents as proteinuria, often leading to nephrotic syndrome. Edema is common and may be due to cardiac failure or nephrotic syndrome. 

Autonomic and sensory neuropathies are relatively common complications; autonomic neuropathy producing disorders of GI motility, symptomatic postural hypotension, and impotence. The disease has been linked with amyloid goiter and CREST syndrome.

1. Diffuse skin infiltration 
2. Macroglossia 
3. Loss of hair on scalp 
4. CHF 
5. Arrythmias 
6. Orthostatic hypotension 
7. Angina 
8. MI 
9. Hemorrhage due to infiltration of amyloid in the GI tract 
10. Claudication of legs and jaw 

Approach considerations: 

The deposition of amyloid fibrils in many tissues characterizes systemic light-chain (AL) amyloidosis. The best response rates are achieved when therapy is initiated among patients who have symptomatic organ involvement in the extensive soft-tissue, visceral organs, neuropathy, or coagulopathy. The current standard treatment is in the form of a regimen with daratumumab combined with cyclophosphamide, bortezomib, hyaluronidase, and dexamethasone. Also to be considered is autologous stem cell transplantation in eligible patients, especially those not having achieved the goal of a complete response to initial therapy. The goal of treatment should be a complete hematologic response, defined as a difference between the involved and uninvolved free light chains (FLC) of less than 10 mg/L or involved FLC of less than 20 mg/L. Treatment modifications should be considered if there is not at least a very good partial response after three cycles, or a partial response after two cycles. In addition, all individuals with AL amyloidosis should be assessed for current clinical trial opportunities, as several promising novel approaches to treatment are being tested. 

Medical care: 

Treatment of primary systemic amyloidosis is based on the affected organ and the type of disease. It is treated with chemotherapy regimens similar to myeloma. Daratumumab is the first and only specific treatment to have been approved in 2021 by the FDA for newly diagnosed AL amyloidosis. The recommended regimen for the first-line treatment is a subcutaneous formulation of daratumumab plus hyaluronidase in combination with dexamethasone, bortezomib, and cyclophosphamide. In the ANDROMEDA trial, the hematologic complete response rate after D-VCd treatment was 42.1%. However, the drug is not recommended for patients with NYHA class IIIB or class IV heart failure or Mayo stage IIIB AL amyloidosis, outside of controlled clinical trials. Second-line treatment would be guided by considerations including initial response, use of new agents, and limitations imposed by frailty/fitness of patients and end-organ damage. 

Dermatology, General

Temperature control: To ease symptoms like perspiration as well as shivers that this disease might be characterized by, it is advisable to ensure that the temperature of the room is always steady and pleasant to avoid cases of amyloidosis. 

Comfortable seating and safe mobility: To reduce discomfort, especially if the patient has neuropathy or joint pain, provide supportive and ergonomic seating. Make sure there are no trip hazards, and that the area has handrails or other mobility aids, particularly if the patient struggles with balance. 

Nutritional support: Modify the surroundings to make it easier to obtain wholesome food and vitamins. If swallowing is a problem due to dysphagia, consider adjustments such as soft foods or thicker beverages. 

Hygiene and personal care: To promote personal hygiene and care, the surroundings need to be altered, and this may include having easily accessible restrooms and tools for dressing or bathing. 

Dermatology, General

Prednisone: It is an immunosuppressant used in treating autoimmune disorders. It may reduce inflammation via reversal of elevated capillary permeability and blocking activity of PMN. 

Dexamethasone: This medication is used in induction and reinduction therapy to lysosomal membranes, stabilizes cell, increases serum levels of vitamin A. It inhibits proinflammatory cytokines and prostaglandins, inhibits chemotactic factors and improves pulmonary microcirculation. However, it also has significant adverse effects including increased inflammatory cell recruitment, suppression of lymphocyte proliferation, and potential side effects during continuation therapy. 

Dermatology, General

Melphalan: This drug is known to inhibit mitosis via cross linkage of DNA strands. 

Dermatology, General

Colchicine: It reduces the motility of leukocytes and decreases phagocytosis during response to inflammation. 

Dermatology, General

Lenalidomide: It resembles to thalidomide structurally. It has antiangiogenic and immunomodulatory effects. It inhibits the secretion of proinflammatory cytokines and enhances the production of anti-inflammatory cytokines from peripheral blood mononuclear cells.  

Dermatology, General

Hyaluronidase/ Daratumumab: This is a monoclonal antibody that attaches itself to CD38, a molecule found in high levels on clonal plasma cells in light chain (AL) amyloidosis among other cells.  

It can be used in conjunction with dexamethasone, bortezomib, and cyclophosphamide for newly diagnosed light chain amyloidosis treatment. 

Dermatology, General

Treatment of PSA requires a number of steps to optimize patient care. The first step is diagnosis and assessment, which can be performed using the few diagnostic tests, where we can confirm amyloid deposits, and if possible, the type. This includes two types of important initial treatments: induction therapy using new drugs, for instance, bortezomib, daratumumab, dexamethasone, and cyclophosphamide. Supportive care follows symptom control and management of complications. 

In the third phase, use is made of response monitoring for continual evaluation of the treatment response and monitoring of side effects. Changes to the treatment are appropriately made based on response and tolerance, with supportive measures continued to treat complications and to help organ function. 

The fourth phase involves consolidation ASCT therapy in eligible patients. Long-term management involves close monitoring, management of chronic problems related to the disease or its treatment, and participation in clinical trials for the use of new treatments and to advance the field. 

Each of these stages represents a crucial aspect of appropriate management of PSA into the equation for better patient outcomes. If all the above stages were followed meticulously, then the management of PSA would be much more proficient and helpful to patients.