AA amyloidosis in inflammatory joint diseases: A systematic review

Journal: Seminars in Arthritis and Rheumatism

First author: Binta Savadogo

Country of study: France — international systematic literature review

CEREMAIA Tenon author: Sophie Georgin-Lavialle

Reference: Savadogo B, Fahed H, Sellam J, Georgin-Lavialle S, Fautrel B, Mitrovic S. AA amyloidosis in inflammatory joint diseases: A systematic review. Seminars in Arthritis and Rheumatism. 2025;74:152762.

DOI: https://doi.org/10.1016/j.semarthrit.2025.152762

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1016%2Fj.semarthrit.2025.152762

5 key points

1. AA amyloidosis can occur when inflammation remains high for a long time in some inflammatory joint diseases.

2. The kidneys are often the main organs affected, which may cause protein loss in the urine and reduced kidney function.

3. The review suggests that AA amyloidosis appears to have become less frequent in some diseases since the introduction of more effective treatments.

4. Treatments that control inflammation well, especially biologic therapies, may improve markers such as serum amyloid A and kidney function.

5. The authors highlight the lack of recent data and the need to better measure the current burden of this complication.

Introduction

AA amyloidosis is a complication of chronic inflammation. It occurs when an abnormal protein called amyloid builds up in organs, especially the kidneys, but sometimes also the digestive tract, liver or heart. It may complicate inflammatory joint diseases such as rheumatoid arthritis, spondyloarthritis, psoriatic arthritis or juvenile idiopathic arthritis. Because modern anti-inflammatory treatments have greatly improved, the authors wanted to know whether this complication has become less common.

Methods

The authors performed a systematic literature review. They searched several medical databases up to October 2024 for studies describing patients with biopsy-confirmed AA amyloidosis related to inflammatory joint disease. Included studies had to report at least 10 patients and provide information on frequency, mortality or evolution under treatment.

Results

In total, 33 studies were included, representing almost 14,000 patients with inflammatory joint diseases. The data were very heterogeneous, and most studies were old, published before 2010. In rheumatoid arthritis, reported AA amyloidosis prevalence ranged from 16.7% to 25.2% before 2010 and appeared to decrease to 0.7% after 2010. In ankylosing spondylitis, reported prevalence ranged from 6.1% to 8.5% before 2010 and from 1.1% to 1.3% after 2010. Immunomodulating treatments, especially biologic therapies, seemed to improve some markers of AA amyloidosis.

Discussion

These findings suggest that better control of inflammation may reduce the risk of AA amyloidosis or improve its course. However, the authors remain cautious because available studies are old, very different from one another and do not allow firm conclusions. The article also emphasizes the importance of monitoring chronic inflammation and kidney function in patients with inflammatory joint diseases.

Conclusion

AA amyloidosis now appears to be less frequent than in the past in some inflammatory joint diseases, probably thanks to more effective treatments. Recent, larger and better standardized studies are needed to better understand the current risk and improve prevention.

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1016%2Fj.semarthrit.2025.152762

A missense mutation in the SAA1 protein causing hereditary amyloid A Amyloidosis

First author: Nelson Leung

Journal: Kidney International (2026), 110:255–259

PubMed link: https://pubmed.ncbi.nlm.nih.gov/41887599/

Summary by Prof. Sophie Georgin-Lavialle and Dr Rim Bourguiba

Key points

• Description of a familial form of AA amyloidosis due to a heterozygous SAA1 mutation.

• The presentation is unusual because there is no inflammatory syndrome and circulating SAA levels are normal or low.

• The p.D34V mutation markedly increases SAA1’s ability to form amyloid fibrils.

• This abnormality may not be detected by standard proteomic typing.

• A genetic cause should be considered in familial AA amyloidosis or AA amyloidosis without an obvious inflammatory cause.

Summary

This article reports a family affected by hereditary AA amyloidosis linked to an SAA1 mutation. The index case is a 37-year-old man investigated for significant proteinuria; kidney biopsy showed AA amyloid deposits. However, the presentation did not match “classic” AA amyloidosis: there was no inflammatory syndrome, no CRP elevation, and circulating SAA was below the detection threshold. The family history was highly suggestive, with several relatives affected by renal or systemic amyloidosis and early deaths, pointing toward autosomal dominant inheritance.

Whole-exome sequencing identified in affected individuals a heterozygous missense variant in SAA1, c.101A>T, leading to the p.D34V substitution. This variant was absent in the unaffected father and not present in population databases. Prior genetic investigations for an autoinflammatory disease were negative. The authors emphasize that this variant lies in a genomic region that can be masked in some standard analyses, creating a risk of missed diagnosis.

The work is also methodologically noteworthy. With conventional mass spectrometry, deposits were typed as AA amyloidosis with predominance of SAA1, but without detection of the mutant protein. In fact, the D34V substitution lies between two tryptic cleavage sites, making the mutant peptide difficult to detect with standard workflows. Using an alternative digestion with Asp-N enabled identification of the mutant peptide in amyloid deposits. Importantly, deposits preferentially contained the mutant form of SAA1, suggesting it aggregates much more readily than the wild-type protein.

Structural and functional analyses were consistent with this. The mutation replaces a negatively charged aspartic acid with a hydrophobic valine in a region important for fibrillogenesis. This change destabilizes the native structure of SAA1 and promotes its conversion into amyloid fibrils. Experiments with synthetic peptides showed a clear increase in aggregation of the mutant peptide, with higher Thioflavin T signal and abundant fibrils on electron microscopy, whereas the wild-type peptide aggregated little under the same conditions.

Overall, this work describes a new cause of hereditary AA amyloidosis, independent of chronic inflammation and driven by the intrinsic amyloidogenicity of mutant SAA1. Clinically, the message is important: in AA amyloidosis without an obvious inflammatory cause - especially in younger patients and/or in the presence of a family history - a genetic etiology should be considered and the SAA1 gene carefully analyzed. This observation also raises management questions, as usual AA amyloidosis treatments aimed at reducing SAA production (e.g., anti–IL-6 therapies) may have limited efficacy in this context.

Renal amyloidosis in Norway: how the disease has evolved over 30 years

English title: Epidemiology and clinical presentation of kidney amyloidosis have changed over the past three decades: a nationwide population-based study

First author: Hilde J. Vasstrand

Journal : BMC Nephrology

Reference : BMC Nephrol. 2025 Jun 2;26(1):272.

PubMed link : https://pubmed.ncbi.nlm.nih.gov/40457206/

Article summarized by: Dr Catherine Grandpeix-Guyodo

Introduction:

Amyloidoses are diseases related to protein deposits in the form of amyloid fibrils. Protein typing helps understand the presentation of the disease, its progression, prognosis, and allows treatment adaptation. Early diagnosis of kidney amyloidosis is essential for treatment optimization and prognosis improvement. This Norwegian nationwide study conducted over 30 years explores changes in the epidemiology and clinical presentation of kidney amyloidosis to raise awareness about these conditions.

Patients and methods: Over a 30-year period, 479 patients with amyloidosis on kidney biopsy were identified in the registries, including 209 AA amyloidoses (SAA protein deposits) and 270 non-AA amyloidoses (mainly AL amyloidoses from immunoglobulin light chain deposits). Patient records were studied and cases were separated into AA amyloidosis and non-AA amyloidosis.

Results:

The frequency of renal amyloidosis was stable over time (4% of kidney biopsies), but AL amyloidosis became the predominant form of non-AA amyloidoses with a frequency increasing from 1.9% to 2.8% of kidney biopsies (p = 0.014). In parallel, the proportion of AA amyloidosis decreased from 2.6% to 1.3% (p < 0.001), due to the reduction in amyloidoses secondary to inflammatory rheumatic diseases, partly offset by AA amyloidoses secondary to drug injections.

Advances in typing amyloid deposits significantly reduced undetermined amyloidoses (p < 0.001) and led to more precise diagnoses. Clinical presentations were varied, but proteinuria was present in 94% of patients. Nephrotic syndrome was noted more frequently in patients with non-AA amyloidosis (70%) than in those with AA amyloidosis (51%). Kidney function was better preserved in non-AA amyloidoses (median GFR 53 ml/min/1.73 m²) than in AA amyloidoses (median GFR 27 ml/min/1.73 m²). Patients with AA amyloidosis were younger (p < 0.001) and more often hypertensive (53% versus 38%, p < 0.001).

Regarding patients developing AA amyloidosis following drug injection, they were younger, more often male, and presented more advanced kidney disease with half in end-stage kidney disease.

Recently, the authors noted that patients with non-AA amyloidosis had better albumin, hemoglobin, and ESR levels (p < 0.05). Additionally, the proportion of non-AA amyloidosis with end-stage kidney disease dropped from 26.8% to 8.7% (p = 0.005), which could indicate earlier diagnoses.

Conclusion:

There have been changes in the epidemiology of kidney amyloidosis in Norway over the past 30 years. The rate of non-AA amyloidosis in biopsies has increased, and certain indicators suggest that diagnosis is made earlier. Amyloid typing has improved, which is reflected in more precise diagnoses with a decrease in undetermined forms. AA amyloidoses related to inflammatory rheumatic diseases have significantly decreased, but the increase in AA amyloidoses in patients who inject drugs is becoming a growing problem.

Awareness of amyloidoses remains necessary, especially during this period when epidemiology is changing with, as a consequence, the possibility of changes in clinical presentation and therapeutic needs.