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.

Familial Mediterranean Fever (FMF) and psoriatic arthritis: a higher risk than expected

Article title: Increased risk of psoriatic arthritis in patients with familial Mediterranean fever: a population-based cohort study.

First author: Amir Haddad

Journal: Rheumatology (Oxford)

Link to the article: https://doi.org/10.1093/rheumatology/keaf607

Author of the abstract: Dr Rim Bourguiba

Summary

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is associated with mutations in the MEFV gene and characterized by excessive activation of the interleukin-1 (IL-1)β pathway. Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the spectrum of spondyloarthritis, whose pathophysiology notably involves the IL-23/IL-17 pathways and Th17 lymphocytes. Data concerning the association between FMF and PsA have remained limited until now.

This retrospective population-based cohort study was conducted using the database of the main Israeli health insurance organization (Clalit Health Services), covering approximately 4.9 million individuals, between 2010 and 2023. The authors identified 9,736 adults with FMF treated with colchicine, with no history of PsA, matched by age and sex to 97,360 non-FMF controls. Participants were followed until the occurrence of PsA, death, or the end of the study period.

The incidence of PsA was significantly higher in FMF patients than in controls (3.26 vs 0.9 per 1,000 person-years). After adjustment for demographic factors and comorbidities, FMF was associated with a more than three-fold increased risk of developing PsA (HR 3.52; 95% CI 2.48–5.0). Other factors independently associated with PsA in FMF patients were age, smoking, and high socioeconomic status. The presence of psoriasis was, as expected, the major predictive factor.

The clinical characteristics and therapeutic strategies of PsA were overall similar in patients with or without FMF, with the exception of more frequent use of targeted synthetic DMARDs in FMF-PsA patients.

These results suggest an increased susceptibility to PsA in FMF patients, possibly related to common immunopathological mechanisms involving IL-1β and Th17 activation. They highlight the need for increased clinical vigilance regarding inflammatory joint manifestations in FMF patients.

In practice, this work encourages active screening for symptoms suggestive of psoriatic arthritis (persistent joint pain, enthesitis, dactylitis) in patients with FMF, particularly in cases of psoriasis or associated risk factors.

CAPS: Improving Our Understanding of a Rare Inflammatory Disease Caused by a Partial NLRP3 Gene Mutation

Summary by: Dr Yixiang Yves-Jean Zhu

First author: Bonet N.

Journal: Journal of Clinical Immunology

Reference: J Clin Immunol. 2025 Sep 30;45(1):134. doi: 10.1007/s10875-025-01922-x

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/41026232/

Introduction:

Cryopyrin-associated periodic syndrome (CAPS) is a rare monogenic autoinflammatory disease associated with gain‑of‑function variants in the NLRP3 gene. These variants lead to constitutive activation of the corresponding inflammasome and excessive production of IL‑1β. The classic manifestations combine a urticaria‑like rash, arthralgia, recurrent fever, neurologic involvement, and sensorineural hearing loss, in a context of biological inflammation (elevated CRP). Within the clinical spectrum of CAPS, Neonatal Onset Multisystem Inflammatory Disease (NOMID) stands out because of its particular severity. Current treatment relies on IL‑1β‑blocking agents, and specific *NLRP3* inflammasome inhibitors such as MCC950 are under investigation. Transmission is usually autosomal dominant, but some cases result from post‑zygotic mutations leading to mosaicism, a phenomenon that remains poorly documented. This retrospective Spanish study reports the largest cohort to date of CAPS patients with NLRP3 mosaicism, providing clinical, genetic, and functional analyses of 17 patients.

Main results:

-Clinical characteristics: Seventeen individuals (7 men, 10 women) were included. Four had a NOMID phenotype, 14 had a CAPS phenotype other than NOMID, and one individual was asymptomatic. The mean age at onset was 26 years (range 0.1–76 years), with two patient subgroups: an early‑onset group (< 5 years) including 6 patients, and a late‑onset group (> 45 years) including 6 patients. The most frequent manifestations were a urticaria‑like rash (100%), arthralgia (87%), recurrent fever (75%), arthritis (68%), and headache (56%).

- Response to treatment: All symptomatic patients received an IL‑1 inhibitor: anakinra (14 patients) or canakinumab (2 patients). A complete response with CRP normalization and clinical improvement was observed in 94% of patients. One case with partial response to anakinra was successfully controlled after switching to canakinumab.

- Genetic and functional data: Sixteen different NLRP3 variants were identified, all located in exon 4, with allele frequencies ranging from 1.3% to 34.8%. In vitro studies confirmed hyperactivation of the inflammasome, which was sensitive to the specific NLRP3 inhibitor MCC950, except for the D303H variant, which was partially resistant.

- Clonal evolution: Longitudinal follow‑up showed stable allele frequency in 54% of cases, an increase in 23% (mainly in patients older than 50 years, suggesting possible clonal hematopoiesis carrying the pathogenic NLRP3 variant, and a decrease in 23%, which may reflect “fatigue” of the mutant clone.

- Distribution of mosaicism: In 64% of patients, mosaicism involved at least myeloid and lymphoid cells, while 36% had mosaicism restricted to myeloid cells. No major clinical differences were observed between these mosaic patterns.

Practical message:

This largest‑to‑date study of mosaic CAPS shows that:

- The clinical picture and treatment response are comparable to those of germline CAPS, and functional studies reveal a similar activation profile.

- Mosaicism may remain stable or fluctuate over time, and the usefulness of monitoring allele frequency for follow‑up remains to be determined.

- Mosaicism may be restricted to myeloid cells, suggesting a later‑acquired variant, without apparent impact on clinical features.

A diagnosis of CAPS should not be ruled out in patients with a compatible phenotype solely on the basis of negative family history. Screening for NLRP3 mosaicism is essential in any adult with a suggestive CAPS presentation, as these patients also show an excellent response to IL‑1 inhibitors. Because mosaicism is more sensitively detected by high‑throughput sequencing, this technique should be preferred when CAPS is suspected, with sufficient read depth to identify low‑frequency allele mosaicism.