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Anti-proinflammatory cytokine biotherapy can prevent the progression of AA amyloidosis to end-stage renal disease.

First author: Kvacskay P

Revue : Annals of Rheumatic disease

Reference:  PMID: 38653531 ; DOI: 10.1136/ard-2023-225114


 

Introduction:

AA amyloidosis (AA) can be the consequence of any chronic inflammatory disease. AA is associated with chronic inflammatory diseases (cid+AA), autoinflammatory syndromes (auto+AA) or AA of unknown origin or idiopathic AA (idio+AA). The major organ manifestation is renal AA that can progress to end-stage renal disease (ESRD) and multiple organ failure.


Materials and methods:

This study is a monocentric retrospective analysis of the renal outcome and survival of patients with cid+AA (n=34), auto+AA (n=24) and idio+AA (n=25) who were treated with cytokine-inhibiting biological disease-modifying antirheumatic drugs (bDMARDs).


Results

83 patients with renal AA amyloidosis were identified and followed for a mean observation period of 4.82 years.

The patients were 34 with cid+AA (40.5%), including 18 with rheumatoid arthritis and 8 with chronic inflammatory bowel disease; 25 with idio+AA (30.5%) and 24 with auto+AA (29%), including 22 with familial Mediterranean fever and 2 with cryopyrinopathies.

Levels of C-reactive protein (CRP), serum amyloid A protein (SAA) and proteinuria were significantly reduced under treatment with biotherapy.

With biotherapy, progression to ESRD was prevented in 88% of patients in the auto+AA group, 81% in the idio+AA group and 60% in the cid+AA group during the study period.

Thirty-four patients received tocilizumab in the cid+AA (n=18) and idio+AA (n=16) arms. Tocilizumab was more effective in reducing CRP and progression to ESRD and death than other biotherapies. No patient taking tocilizumab during the study period died.

Patients with autoinflammatory diseases were excluded from this analysis with tocilizumab as this biotherapy is not indicated for inflammatory diseases.


Conclusion


Anti-proinflammatory cytokine biotherapies reduce systemic inflammation in various diseases associated with the development of AA amyloidosis, leading to a reduction in proteinuria and prevention of ESRD.


In this retrospective series, tocilizumab tested in 34 patients with AA amyloidosis complicating chronic or idiopathic inflammatory disease was more effective than other biotherapies in controlling systemic inflammation, leading to improved renal and overall survival in these patients.


Figures


Figure 1. Serum biomarkers and proteinuria are analysed in subgroups of AA patients with chronic inflammatory disease cid+AA (cid+AA), autoinflammatory disease auto+AA (auto+AA) and idiopathic disease (idio+AA).


Biotherapy was initiated at the first visit (baseline) and compared with the last documented visit 4 to 6 years later. CRP (A), SAA (B), serum creatinine (C), sample proteinuria (D), serum albumin (E), total serum protein (F), serum IgG (G) and NT-BNP (H) were analysed at the first and last visits.

Figure 1


Figure 2: Patients treated with Tocilizumab (TOC) were compared with other biotherapies.


(A): Patients with cid+AA (cid+AA) and idio+AA were followed every 6 months until the last visit.

(B) and (C): Analyses of cid+AA (cid+AA) and idio+AA subgroups are shown. (D) Across the cohort tocilizumab (TOC) prevented progression of AA to other organs and death (D).


Figure 2

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Development and Validation of Staging Systems for AA Amyloidosis

First author:  Basset et al

Review:  Journal of the American Society of Nephrology

Reference :  DOI :   10.1681/ASN.0000000000000339


Introduction:


Inflammatory amyloidosis is a rare disease secondary to the deposition of serum amyloid A (SAA) protein in the form of insoluble amyloid fibrils, causing predominantly renal damage and dysfunction that may progress to end-stage renal disease requiring dialysis. Renal involvement is almost constant in all cases of AA amyloidosis at the time of diagnosis, while cardiac involvement is uncommon. Unlike the more common forms of systemic amyloidosis, particularly AL and ATTR, AA amyloidosis has not yet been the subject of prospective studies.


Thanks to their ability to accurately predict prognosis without the need for invasive and expensive tests, stratification systems based on biomarkers are playing a well-established role in the management of patients with systemic amyloidosis. For example, stratification systems for overall survival and renal failure have been validated for AL amyloidosis. More recently, two overall survival stratification systems have been validated for transthyretin amyloidosis (ATTR). However, AA amyloidosis has not yet had a validated system for stratifying the risk of renal progression of the disease. In this study, the authors developed and validated a stratification system for overall survival and renal failure in patients with newly diagnosed AA amyloidosis.

 

Methods :


Patients included.


The databases of the Amyloidosis Research and Treatment Centre in Pavia, Italy, and the Amyloidosis Centre in Heidelberg, Germany, were used. Four hundred and seventy-six consecutive patients with newly diagnosed AA amyloidosis, including 233 in Pavia between 1991 and 2020 and 243 in Heidelberg between 1975 and 2020, were included in the study.


In the absence of a specific consensus on the definition of organ involvement in AA amyloidosis, the authors chose to use the criteria for organ involvement in AL amyloidosis: glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and N-terminal BNP (NT-proBNP).


The Italian cohort was used as the test population and the German series as the validation cohort in the analysis.

 

Statistical analysis


ROC analyses based on survival, death and dialysis of patients with AA amyloidosis at 24 months were used to identify biomarker thresholds, which according to the Youden index, best discriminate between overall survival and renal failure. Median follow-up was estimated using the inverse Kaplan-Meier method. Overall survival was calculated from diagnosis to death (event) or last contact with the living patient.


The stratification system developed in the Pavia cohort was applied to the Heidelberg cohort. Given the good discrimination and calibration, the authors combined the two cohorts for subsequent analyses, in order to make effective use of the information contained in the risk categories and to increase the precision of the associated HR estimates.

 

Results:

A total of 476 patients were evaluated during the study period (233 in Pavia and 243 in Heidelberg), most of whom (>95%) were diagnosed after 2000 (Table 1). Renal involvement was present in 95% of cases; 33 Italian (14%) and 47 German (19%) patients were already on dialysis at the time of diagnosis respectively.


Differences were observed between the two cohorts: serum albumin levels were higher and German patients were younger than Italian patients. Differences were also observed in the underlying causes of chronic inflammation, with a higher proportion of recurrent infections and idiopathic AA in Italy and more autoinflammatory diseases in Germany. t .


The median follow-up of patients was 67 months in Italy and 36 months in Germany. In the Italian cohort, 58 (25%) patients died and 51 (21%) in the German cohort. No difference in overall survival was observed between the two cohorts (Log-rank test p=0.28).


Among patients who were not on dialysis at the time of diagnosis, 68 (32%) progressed to end-stage renal disease in the Pavia group and 56 (29%) in the Heidelberg cohort.

 

Identification of biomarker thresholds that best discriminate between overall survival and renal failure


The most discriminating thresholds for overall survival at 24 months in the Pavie test cohort were


- eGFR 45 ml/min/1.73 m2


- 3.0 g/dL for serum albumin


- 40 mg/L for SAA


- 130 ng/L for BNP


- 1000 ng/L for NT-proBNP


The most discriminating thresholds for dialysis at 24 months were


- GFR at 35 ml/min/1.73 m2


- 3.0 g/dL for serum albumin


- 25 mg/L for SAA


- 3 g/24h for 24-hour proteinuria


Prediction of overall survival and stratification system (Table 2)


The stratification system calculated as the sum of the simplified coefficients ranged from 0 to 3. Because of the low number of deaths in certain categories, the authors grouped score 0 with score 1 (low-risk category). This stratification system identified three groups of patients with significantly different survival.


Overall survival at 5 years was 94% (95% CI: 87-98%) in the low-risk category, 80% (95% CI: 62-90%) in the intermediate-risk category and 46% (95% CI: 21-68%) in the high-risk category.


 

Discussion and conclusion:

This is the first study to propose a stratification system based on non-invasive biomarkers for overall survival and renal failure in AA amyloidosis.


Older age at diagnosis, 24h proteinuria, proteinuria/creatinuria ratio


were confirmed as poor prognostic factors for survival and progression to renal failure.


In conclusion, the authors propose these biomarkers for stratifying overall survival and renal failure with the aim of improving the management of patients with AA amyloidosis by identifying the most severe cases.



Table 2

Table 4

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Frequency of AA amyloidosis has decreased in Behçet’s syndrome: a retrospective study with long-term follow-up and a systematic review: Amyloidosis in Behçet’s syndrome

Updated: Jun 2

First author : G Karatemiz

Review : Rheumatology


Introduction:

Inflammatory rheumatic diseases are a classic cause of inflammatory amyloidosis (AA). Behçet's disease is a multi-systemic vasculitis that affects vessels of all calibres. Although uncommon in Behçet's disease, AA amyloidosis is at high risk of mortality and is one of the main causes of renal failure in Behçet's disease. The authors' aim was to determine the frequency of AA amyloidosis in patients with Behçet's disease, and identify clinical and therapeutic demographics.

Methods:

Patients with Behçet's disease complicating with AA amyloidosis in Turkey were included. The primary endpoints were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered between 1976 and 2000 and those registered between 2001 and 2017, to determine whether there was a change in frequency.

A systematic review of the literature on cases of AA amyloidosis complicating Behçet's disease accompanied this study.

Results:

Between 1976 and 2017, a cohort of patients with Behçet's disease (n=9410) was followed of whom, 27 (0.29%) developed AA amyloidosis.

Between 1976 and 2000, a cohort of 3,820 patients with Behçet's disease was followed; 24 patients (0.62%) developed AA amyloidosis.


Between 2001 and 2017, of the 5590 patients followed for Behçet's disease, 3 developed AA amyloidosis (0.054%).

The incidence of AA amyloidosis increased from 0.62% to 0.054% (P < 0.0001).

Co-morbidities that may be associated with amyloidosis were tuberculosis (n= 2), FMF

FMF (n=1) and spondyloarthritis (n=1). MEFV gene sequencing had been performed in 2 patients showing no pathogenic variant, and one of them was heterozygous for the M680I mutation.

Prior to the diagnosis of AA amyloidosis, 19 patients (70%) were on colchicine, 15 patients were on immunosuppressants and 2 on corticosteroids only. At the time of amyloidosis diagnosis, 12 patients were off treatment, 8 were using an immunosuppressant (5 AZA, 2 CYC and 1 MTX), and 2 were using CS only.

Outcome:

Fourteen patients (52%) died after a median follow-up of 3 years (IQR: 7.75), 3 were lost to follow-up and 10 (37%) were still alive after a median follow-up of 11 years

(IQR: 16). The reasons for death were infections in 5 cases, complications related to end-stage renal failure in 5 cases, subarachnoid haemorrhage, gastric adenocarcinoma, cirrhosis associated with amyloidosis and iatrogenic intestinal perforation in one case each. Nine (64%) of the 14 patients who died had developed end-stage renal disease (ESRD).


Overall, 15/27 patients (55.5%) developed ESRD after a median follow-up of 3.5 years (IQR: 5.25) after diagnosis of AA amyloidosis. Five patients underwent renal transplantation.

A systematic review of the literature revealed 82 cases in 42 publications. The main characteristics of the patients were a predominance of males and a high frequency of vascular involvement. One third of patients died within 6 months of diagnosis of AA amyloidosis (table 1).

Discussion and conclusion:

According to the results of this study, the frequency of AA amyloidosis in patients with Behçet's disease appears to be decreasing. Male patients with major organ involvement, particularly vascular involvement, appear to be more likely to develop AA amyloidosis. Although AA amyloidosis rarely complicates Behçet's disease, its occurrence is observed in younger patients and it appears to worsen the overall prognosis of the disease.

 


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