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Unsupervised clustering of undifferentiated systemic autoinflammatory diseases (USAID)

Jeanne CHAUFFIER
Oct 18
1 min read
Mieux comprendre et regrouper les maladies auto-inflammatoires systémiques d’origine indéterminée

First author: Jeanne Chauffier

Journal: European Journal of Internal Medicine

Summary author: Jeanne Chauffier


Background:   

Undifferentiated systemic autoinflammatory diseases (USAID) comprise a heterogeneous group of disorders characterized by recurrent systemic inflammation without an identifiable monogenic cause.  


Objective:  

To describe the phenotypic and therapeutic features of adult USAID and identify phenotypic clusters. 


Methods: 

We conducted a retrospective single-center study at the French Reference Center for Autoinflammatory Diseases between 2010 and 2025. USAID was defined as recurrent systemic attacks with ≥3 documented C-reactive protein (CRP) elevations and no pathogenic variant identified. Therapeutic response was classified as complete (CR) or partial (PR). Hierarchical cluster analysis included clinical and biological variables. 


Results:  

Among 150 patients (65.3% women; median age at onset 14 [0–64] years), recurrent attacks occurred in 87.3%. The most frequent manifestations were cutaneous (87.3%), fever (84%), asthenia (80%), musculoskeletal (79.3%), and abdominal involvement (63.3%). Colchicine was prescribed in 56.7% (CR 8.2%, PR 44.7%). Biologic therapies included anti-TNFα (n = 32; CR 21.9%, PR 31.3%), anti-IL-1 (n = 24; CR 25%, PR 16.7%), anti-IL-6 (n = 22; CR 31.8%, PR 31.8%), and JAK inhibitors (n = 16; CR 18.8%, PR 37.5%). 

Four clusters were identified:  

Cluster 1 (15.3%): fever, aphthous ulcers, pharyngitis, abdominal pain and lymphadenopathy.  

Cluster 2 (27.3%): brief attacks, frequent urticaria and abdominal pain.  

Cluster 3 (18.7%): prolonged attacks, prominent arthralgia, arthritis, and myalgia.  

Cluster 4 (38%): predominantly men, higher age at the onset, frequent neutrophilic dermatoses.  

Treatment responses did not differ significantly between clusters.  


Conclusion:  

Adult USAID patients can be subdivided into four clusters. Phenotypic stratification may help structure diagnostic reasoning and guide future therapeutic research. 


 


 
 
 

How (Ultra-)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases

Jeanne CHAUFFIER
Jul 19
2 min read

Journal: ACR Open Rheumatology

First author: Alexandre Belot

Country of study: France, United Kingdom — international narrative review

CEREMAIA Tenon author: Sophie Georgin-Lavialle

Full reference: Belot A, Tusseau M, Cognard J, Georgin-Lavialle S, Boursier G, Hedrich CM. How (Ultra-)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases. ACR Open Rheumatology. 2025;7(2):e70003.


How (Ultra-)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases

5 key points

1. Rare mutations in a single gene can cause specific forms of lupus or Behçet syndrome.

2. Studying these rare forms helps explain the immune mechanisms involved in more common diseases.

3. In monogenic lupus, several rare genetic defects interfere with the clearance of cell debris or cause excessive interferon activity, a key driver of inflammation.

4. In Behçet syndrome, some rare variants highlight the major role of the NF-κB pathway, which is involved in immune activation.

5. Better understanding of these genetic abnormalities may support more targeted treatments and more personalized medicine.


Introduction

Inflammatory diseases such as systemic lupus or Behçet syndrome are usually complex and linked to several genetic and environmental factors. However, in a small number of patients, a single rare genetic abnormality may play a major role. This article explains how studying these rare forms can improve our understanding of the more common forms of these diseases.


Methods

This is a narrative review. The authors summarize current knowledge about rare and ultra-rare genetic variants involved in monogenic forms of lupus and Behçet syndrome, with a focus on biological mechanisms and the consequences for research and patient care.


Results

In lupus, several rare genetic abnormalities have highlighted important mechanisms: poor clearance of cell debris, complement defects, abnormal DNA or RNA regulation, excessive type I interferon activity, overactivation of immune pathways such as TLR or JAK/STAT, and loss of immune tolerance. In Behçet syndrome, rare variants in genes such as **TNFAIP3**, **RELA**, or **NFKB1** have shown the central role of another inflammatory pathway called **NF-κB**. Other rarer abnormalities further confirm the diversity of possible disease mechanisms.


Discussion

The article shows that diseases that look similar clinically may actually have different biological causes. This helps improve disease classification, explain early, severe or unusual cases, and identify more precise treatment targets. In practice, genetics may be especially useful in younger patients or in patients with atypical or familial forms.


Conclusion

Studying rare variants is not only important for exceptional cases: it also improves our understanding of more common inflammatory diseases. In the future, this approach may support more accurate diagnosis and treatments that are better tailored to each patient.


 
 
 

AA amyloidosis in inflammatory joint diseases: A systematic review

Jeanne CHAUFFIER
Jul 7
2 min read

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.


AA amyloidosis in inflammatory joint diseases: A systematic review

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.


 
 
 
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