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BACKGROUND: AA amyloidosis (AAA) remains a life-threatening yet largely preventable complication of monogenic autoinflammatory diseases (AIDs). METHODS: We retrospectively described patients with AAA secondary to one of the four historical monogenic AIDs (familial Mediterranean fever [FMF], cryopyrin-associated periodic syndrome [CAPS], mevalonate kinase deficiency [MKD] and tumour necrosis factor receptor-associated periodic syndrome [TRAPS]) followed at the French National Referral Centre for Monogenic AIDs and Inflammatory Amyloidosis (2012-2025). RESULTS: Among 181 patients followed for AAA, 50 (28%) had one of the four monogenic AIDs (FMF n = 41, CAPS n = 4, MKD n = 3, TRAPS n = 2), corresponding to an overall prevalence of 5% among all patients with monogenic AIDs. AAA preceded the diagnosis of the underlying AID in 40% of patients, particularly those with non-FMF diseases. Disease burden remained high, with 46% of patients requiring kidney transplantation, whereas mortality reached 26% during follow-up. CONCLUSION: AAA continues to reflect delayed diagnosis, highlighting the need for increased awareness among adult healthcare providers, systematic genetic evaluation of unexplained AAA and early inflammatory control.

INTRODUCTION: AA amyloidosis (inflammatory amyloidosis) is a rare but serious complication of chronic inflammatory diseases. Its etiological spectrum is broad, potentially contributing to delayed diagnosis, particularly when the underlying cause is rare or poorly recognized. We developed the AA Challenge, an interactive French-language online educational program based on clinical cases, to improve the recognition of the causes of AA amyloidosis among French-speaking physicians. METHODS: The AA Challenge was an international, year-long educational program for French-speaking physicians. It consisted of monthly interactive clinical case quizzes, each illustrating a different cause of AA amyloidosis or a relevant differential diagnosis. Participants were asked to identify the underlying etiology based on the clinical, biological, and/or imaging data provided. The program was disseminated via email, social media, and the digital platforms of organizations involved in amyloidosis. An international steering committee comprising physicians from ten French-speaking countries contributed to the promotion of the program. Participants also received a monthly literature review on AA amyloidosis. Quiz responses, available participant characteristics, and the results of the final satisfaction survey were analyzed. RESULTS: Twelve clinical cases were released between 2022 and 2023. A total of 2,968 responses were recorded on the Eval&Go® platform. After exclusion of duplicate submissions, 2,597 responses were included in the performance analysis. Information on medical specialty was available for 2,536 responses. Participants were primarily specialists in internal medicine (n=1,534; 59.1%), nephrology (n=470; 18.1%), and rheumatology (n=199; 7.7%). The most represented countries were Morocco (n=646; 24.9%), France (n=537; 20.7%), Romania (n=420; 16.2%), and Tunisia (n=273; 10.5%). Correct response rates varied by etiology, ranging from 29.9% for the AL amyloidosis quiz to 89.0% for the Crohn's disease quiz. The most accurately recognized etiologies were Crohn's disease, rheumatoid arthritis, and spondyloarthritis, whereas AL amyloidosis, tuberculosis-associated bronchiectasis, mevalonate kinase deficiency, cryopyrin-associated autoinflammatory syndromes (CAPS), and primary hyperoxaluria were less frequently identified. The overall correct response rate was 62.1%. The monthly literature review covered 25 publications on AA amyloidosis. The final satisfaction survey received 124 responses and demonstrated a high level of overall satisfaction, with a mean score of 8.61 ± 1.36 out of 10. CONCLUSION: The AA Challenge demonstrates the feasibility and value of an interactive French-language online educational program based on clinical cases designed to increase physicians' awareness of the diverse causes of AA amyloidosis. This initiative highlights the potential of digital educational tools to improve knowledge of rare diseases and could be adapted to other conditions in which earlier or more accurate diagnosis is needed.

OBJECTIVES: Systemic autoinflammatory diseases (SAIDs) arise from genetic defects in innate immunity, leading to dysregulated activation of inflammatory pathways, including interleukin (IL)-1, IL-6, TNF, and JAK/STAT. Clinical manifestations range from recurrent fever to severe complications such as encephalitis and AA amyloidosis. Management aims to control inflammation using immunosuppressive agents and targeted monotherapies (biologics or JAK inhibitors). Advanced combination therapy (ACT), defined as the use of biologics and/or JAK inhibitors in combination, has emerged as a strategy for refractory disease. METHODS: In this observational retrospective longitudinal cohort study, patients with SAIDs treated with ACT were included. Demographic, clinical, treatment, and safety data were collected. Treatment response was assessed using a composite outcome incorporating corticosteroid dose, C-reactive protein (CRP), and clinical improvement and categorized as non-response, partial response, or complete response. RESULTS: Thirty-eight patients (median age 30 years [range 4-76]) were included. The most common indications for ACT were pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), mevalonate kinase deficiency (MKD), and undifferentiated SAIDs. Most patients had disease-related complications and were dependent on glucocorticoids and/or opioids to control inflammation and pain, respectively. Following multiple ACT trials, complete response was observed in 21 patients (55.3%), partial response in 12 (31.6%), and no response in 5 (13.1%). Overall, 65 ACT regimens were administered, most commonly combining IL-1 and TNF inhibitors. Thirty-nine regimens were discontinued because of lack of efficacy, secondary loss of response, or adverse events. At the final follow-up, 26 patients (68%) remained on ACT, with a median treatment duration of 60 months (range, 11-186). CONCLUSIONS: ACT offers significant clinical benefits for patients with difficult-to-treat SAIDs, though challenges such as secondary loss of efficacy and infection risks remain.

Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G > A (p.Val22Met) and c.1063G > C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G > C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.