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Global Translational Medicine AA amyloidosis in rheumatoid arthritis

1.1. Nomenclature of amyloidosis • Chronic reactive inflammatory diseases: Ankylosing
9,15
Amyloidosis syndromes are classified based on the spondylitis, psoriatic arthritis, 8,15,20 and Reiter’s
1
composition of their fibrillar proteins. For example: syndrome.
• Amyloid A (AA) amyloidosis: Caused by deposits • Autoimmune (inflammatory) diseases: Rheumatoid
8,9,15
3,9,15
of AA protein, which is derived from serum AA, an arthritis (RA), juvenile chronic arthritis, adult-
15
acute-phase reactant produced by hepatocytes onset Still’s disease, systemic lupus erythematosus,
21
22
• Amyloid light chain amyloidosis: Results from progressive systemic sclerosis, Crohn’s disease,
23
15
amyloid light chain deposits, which originate from ulcerative colitis, polymyositis , and polymyalgia
24
immunoglobulin light chains (λ or κ) produced by B • rheumatica or giant cell arteritis.
Chronic cachectic diseases and malignancies: Renal cell
cells 15,25,26 27
ovarian carcinoma, hepatocellular
• Amyloid heavy chain amyloidosis: Characterized by carcinoma, bronchial carcinoma, Hodgkin’s
adenoma,
8,31
28-30
amyloid heavy chain (AH) deposits, derived from lymphoma, 32,33 and cardiac (atrial) myxoma. 34
immunoglobulin heavy chains produced by B cells
• Amyloid transthyretin (ATTR) amyloidosis: Caused 1.4. Prevalence, signs, and symptoms of AA
by ATTR deposits, which originate from either altered amyloidosis
wild-type transthyretin (ATTRwt) or genetically
determined mutant transthyretin variants (ATTRm), Secondary or reactive AA amyloidosis accounts for
35
leading to ATTRwt amyloidosis or ATTRm approximately 45% of generalized amyloidosis cases.
amyloidosis Signs and symptoms of amyloidosis vary depending on
• Amyloid β₂-microglobulin amyloidosis: Results from the affected organ. The most commonly involved organs
deposits of amyloid β2-microglobulin, derived from include the gastrointestinal (GI) tract, pancreas, kidneys,
β2-microglobulin, which is produced by lymphoid heart, and liver, with the most extensive deposits typically
cells. occurring in the kidneys, heart, pancreas, GI tract, liver,
and spleen. 3
1.2. Histological characteristics of amyloid
Renal involvement in AA amyloidosis often leads
All amyloid deposits exhibit eosinophilia, congophilia, to massive amyloid deposition, resulting in nephrotic
and birefringence, displaying a characteristic apple-green syndrome. This syndrome, similar to other causes of
color under polarized light. The presence of congophilia nephrotic syndrome, is characterized by impaired kidney
and birefringence remains the gold standard for the function, significant proteinuria, and hypoalbuminemia,
36
microscopic diagnosis of amyloid deposits. While, our which in turn leads to edema, particularly in the lower
2
experience suggests that the intensity of birefringence may extremities. 37,38 Cardiac amyloidosis is associated with
vary between adjacent amyloid deposits, even within the congestive heart failure and arrhythmias. 38
same slide. 3
GI amyloidosis, regardless of the specific amyloid type,
Cohen’s statement 4(pp.649-650) that “there are no commonly presents with symptoms such as abdominal
laboratory abnormalities specific to or unique for pain, dysmotility (atony), malabsorption, diarrhea or
amyloid” remains valid. Furthermore, “there is no one constipation, and GI bleeding. 37,38 Hepatic involvement is
feature in the blood, urine, electrocardiogram, or X-ray frequently accompanied by hepatomegaly and, in some
that is specific for amyloidosis,” and “the diagnosis cases, portal hypertension and its associated complications. 38
should be based upon a biopsy using an appropriate
staining procedure.” 1.5. Literature review
The volume of literature dealing with amyloidosis is
1.3. Underlying diseases associated with AA extensive, with more than 3,000 published articles. Many
amyloidosis
studies have explored the role of chronic inflammation,
Systemic (secondary or reactive) AA amyloidosis occurs in elevated serum AA, plasma levels of misfolded acute-
a wide spectrum of chronic inflammatory diseases, such phase proteins, and the involvement of serum amyloid
5-7
as: P in amyloid fibril formation. 39,40 However, to the best
• Chronic microbial infections: Tuberculosis, leprosy, 10,11 of our knowledge, no studies have specifically examined
8,9
fibrocystic lung diseases, 12,13 bronchiectasis, 9,14,15 the mechanistic understanding of amyloid deposition,
lung abscess, chronic osteomyelitis, chronic the progression of amyloidosis, or the rate of amyloid
8,15
8
xanthogranulomatous pyelonephritis, 16-18 chronic accumulation from a histopathological perspective, apart
mesenteric lymphadenitis, and decubitus ulcers. 9 from our previous publications. 41-43
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Volume 4 Issue 1 (2025) 105 doi: 10.36922/gtm.5325