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

When to suspect monogenic autoinflammatory diseases in patients with digestive symptoms?

Journal: Clinics and Research in Hepatology and Gastroenterology

First author: Rim Bourguiba

Country of study: France and Tunisia

CEREMAIA Tenon author(s): Marion Delplanque, Catherine Grandpeix-Guyodo, Léa Savey, Sophie Georgin-Lavialle

Reference: Bourguiba R, Delplanque M, Grandpeix-Guyodo C, Boursier G, Savey L, Cuisset L, Georgin-Lavialle S. When to suspect monogenic autoinflammatory diseases in patients with digestive symptoms? Clinics and Research in Hepatology and Gastroenterology. 2026;50:102820.

DOI: https://doi.org/10.1016/j.clinre.2026.102820

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1016%2Fj.clinre.2026.102820

5 key points:

• Some rare autoinflammatory diseases can cause abdominal pain, diarrhoea, digestive inflammation or symptoms that resemble inflammatory bowel disease.

• Familial Mediterranean fever is the most common monogenic autoinflammatory disease and should be considered in people of Mediterranean origin with repeated inflammatory abdominal pain.

• Associated signs such as recurrent fever, mouth ulcers, skin rashes, joint pain, macrocytic anaemia or family history should raise suspicion of an autoinflammatory cause.

• Diagnosis is based on clinical assessment, inflammation markers, sometimes IL-18 measurement, and appropriate genetic testing.

• Earlier diagnosis can reduce diagnostic delay, guide treatment and help prevent complications such as AA amyloidosis.

Introduction

Systemic autoinflammatory diseases are rare conditions caused by abnormal activation of the innate immune system, the body’s first line of defence. They can cause flares of inflammation with fever, pain, skin involvement, joint symptoms or digestive problems. In some patients, digestive symptoms are the main feature and may look like inflammatory bowel disease, such as Crohn’s disease.

Methods

This article is a narrative review of the medical literature. The authors describe the main monogenic autoinflammatory diseases that may cause digestive symptoms and highlight situations in which gastroenterologists should consider these diagnoses.

Results

Several diseases can cause abdominal pain, diarrhoea, colitis, digestive ulcers or inflammation that resembles Crohn’s disease. Familial Mediterranean fever is the most common, especially in people of Mediterranean origin. Other conditions include TRAPS, Mevalonate kinase deficiency, cryopyrin-associated diseases, VEXAS syndrome, A20 haploinsufficiency, and diseases linked to RIPK1, RELA, NFKB1, JAK1, STAT, PSTPIP1, ADA2, LACC1, XIAP or PLCG2. Warning signs include recurrent fever, unexplained inflammation in blood tests, mouth ulcers, skin rashes, joint pain, family history, Mediterranean origin, macrocytic anaemia or poor response to usual treatments for inflammatory digestive diseases.

Discussion

The article emphasizes that not all digestive inflammation should automatically be considered a typical bowel disease. An autoinflammatory disease may mimic inflammatory bowel disease, coexist with it, or be revealed by unusual digestive symptoms. Useful investigations may include inflammation markers, endoscopy, specific biomarkers such as IL-18, and above all appropriate genetic testing, ideally discussed with expert centres.

Conclusion

Rare autoinflammatory diseases should be considered when digestive symptoms are inflammatory, unexplained, recurrent or resistant to usual treatments. Early diagnosis can lead to more appropriate care, often using treatments that target inflammation, and may help prevent complications such as AA amyloidosis.

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1016%2Fj.clinre.2026.102820

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.