# Performance of serum IL-18 levels for the follow-up of patients with familial Mediterranean fever

Inès Elhani, Laure Calas, Farah Bejar, Laurence Pieroni, Isabelle Kone-Paut, Linda Rossi-Semerano, Isabelle Melki, Brigitte Bader-Meunier, Bénédicte Neven, Pierre Quartier, et al.

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## To cite this version:

Inès Elhani, Laure Calas, Farah Bejar, Laurence Pieroni, Isabelle Kone-Paut, et al.. Performance of serum IL-18 levels for the follow-up of patients with familial Mediterranean fever. Journal of Allergy and Clinical Immunology: In Practice, 2025, 13 (3), pp.695-697.e1. 10.1016/j.jaip.2024.11.025. hal-04986222

HAL Id: hal-04986222

https://hal.sorbonne-universite.fr/hal-04986222v1

Submitted on 12 May 2025

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Distributed under a Creative Commons Attribution 4.0 International License
Performance of serum IL-18 levels for
the follow-up of patients with familial
Mediterranean fever

<figure><img src="image_3.png" /></figure>

Inès Elhani, MD, PhD<sup>a,b</sup>, Laure Calas, MD<sup>c,d</sup>,
Farah Bejar, MSc<sup>c,d</sup>, Laurence Pieroni, MD<sup>c</sup>,
Isabelle Kone-Paut, MD, PhD<sup>b,e,f</sup>,
Linda Rossi-Semerano, MD<sup>b,e,f</sup>, Isabelle Melki, MD, PhD<sup>g,h</sup>,
Brigitte Bader-Meunier, MD, PhD<sup>e,h,i</sup>,
Bénédicte Neven, MD, PhD<sup>e,h,i</sup>,
Pierre Quartier, MD, PhD<sup>e,h,i</sup>, Guilaine Boursier, MD, PhD<sup>b,j</sup>,
Irina Giurgea, MD, PhD<sup>k</sup>, Laurence Cuisset, MD<sup>l</sup>,
Gilles Grateau, MD<sup>a</sup>, Véronique Hentgen, MD<sup>b,m</sup>,
Philippe Mertz, MD<sup>a,b</sup>, Marion Delplanque, MD<sup>a,b</sup>,
Léa Savey, MD<sup>a,b</sup>, and
Sophie Georgin-Lavialle, MD, PhD<sup>a,b,d,n</sup>

Clinical Implications

Serum total IL-18 levels are elevated in familial Mediterranean fever (FMF) in a gene-dose-dependent manner. It has poor performance in distinguishing disease activity but may indicate low or incorrect colchicine intake in FMF.

Familial Mediterranean fever (FMF) is associated with *MEFV* mutations, leading to excessive activation of the pyrin inflammasome, which is responsible for the production of proinflammatory IL-1β and IL-18. Continuous and/or repeated inflammation can lead to the life-threatening complication of inflammatory (AA) amyloidosis.¹ Disease inactivity is defined as the absence of clinical symptoms and normal values of inflammatory biomarkers. There are several limitations to assessing disease activity. First, flare count may be difficult to assess in some situations (young children and nonspecific symptoms). Elevation of C-reactive protein (CRP) and serum amyloid A (SAA) is not specific to FMF inflammation and may be caused by other inflammatory mechanisms. Finally, CRP and SAA may be dissociated.² IL-18 is a proinflammatory cytokine that is released on inflammasome activation in mononuclear cells.³ Because IL-18 is one of the earliest inflammatory mediators involved in pyrin inflammasome activation in FMF, it is a candidate biomarker for monitoring disease activity. It has been reported that patients with FMF display higher serum IL-18 levels than healthy subjects.⁴⁻⁸ The aims of this study were to describe total serum levels of IL-18 in patients with FMF and to assess its reliability in evaluating disease activity.

We conducted a monocentric retrospective study between
January 2022 and January 2024 at the French reference center
for autoinflammatory diseases (CEREMAIA) in Tenon Hospital,
Paris. Patients with FMF >18 years old who had 1 or more
measurements of serum total IL-18 during routine care were
identified using the Assistance Publique-Hôpitaux de Paris

<figure><img src="image_4.png" /><figcaption>FIGURE 1. Median IL-18/patient levels according to genotype in patients with familial Mediterranean fever. IL-18 levels are significantly lower in patients with heterozygous variants than in both those with compound heterozygous and homozygous variants (\*\*P < .01, \*\*\*P < .001).</figcaption></figure>

Clinical Data Warehouse authorized by the French Data Pro-
tection Authority (Commission Nationale de l'Informatique et
des Libertés, number 1980120).

Age at measurement, sex, *MEFV* genotype, disease activity, inflammatory symptoms, concomitant CRP, and SAA levels were extracted from the database. Disease activity was extracted from medical records as defined by physicians (“controlled” or “uncontrolled”). The center’s physicians routinely use the French guidelines to define disease activity (target <2 flares/year).⁹ Mutational status was defined according to the number of probably pathogenic and pathogenic variants in exon 10 according to the Infevers classification.¹⁰

Total serum IL-18 measurements were obtained during
routine care using a monoclonal antibody-based sandwich
ELISA (Biotechne, R&D Systems, Minneapolis, Minnesota) at
<figure><img src="image_5.png" /><figcaption>FIGURE 2. IL-18 levels according to disease activity. Receiver operating characteristic curve analysis of IL-18 levels to diagnose disease control. AUC, Area under the curve.</figcaption></figure>

the biochemistry laboratory of Tenon Hospital. IL-18 levels are expressed in pg/mL. The median of all measured IL-18 levels was calculated for each patient. Normal IL-18 was defined as <350 pg/mL according to the laboratory.

Variables were expressed as median [range] or as absolute (%) frequencies. Continuous outcomes were compared with the unpaired Student *t* test or the Kruskal-Wallis test according to data distribution. Discrete outcomes were compared with the $\chi^2$ or Fisher exact test accordingly. The alpha risk was set to 5%. Receiver operating characteristic curves were performed to compare the test performance of IL-18 to predict the disease activity and current symptoms. Statistical analysis was performed with EasyMedStat.

We included the data of 308 single total serum IL-18 measurements taken from 208 patients (110 women and 98 men). The median total serum IL-18 level was 922.25 [153.5-22,712] pg/mL. On the measurement day, FMF was reported as inactive in 49% of visits. Patients were treated with colchicine in 96% of cases. Patient and visit characteristics are described in Table E1 (available in this article's Online Repository at www.jaci-inpractice.org).

Median IL-18 levels measured without ongoing symptoms were significantly higher in patients with homozygous variants of *MEFV* than in patients with compound heterozygous or heterozygous variants (< .001, respectively, Figure 1).

We identified 22 patients with measurements taken during both active and inactive disease states. There was no difference in median IL-18 levels according to disease activity (P = .29). Moreover, the performances of IL-18 levels to discriminate disease activity were poor (area under the curve: 0.552 [0.489; 0.615], Figure 2). IL-18 levels were not significantly different when measured with/without current symptoms and with/without a history of inflammatory symptoms the previous month (P = .14 and P = .7, respectively).

Subsequent analyses were performed on homozygous and compound heterozygous subgroups only. Median IL-18 levels/ patient were not significantly different when measured with and without IL-1 blockers (1356 vs 1030 pg/mL, P = .7). Moreover, we identified 13 patients with serum total IL-18 measured before and after starting an IL-1 blocker. There was no difference between IL-18 levels before and after IL-1 blocker initiation (1355 vs 1565 pg/mL, P = .5; Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). In 5 patients, IL-18 decreased after IL-1 blocker initiation by a median of 23% [1.9%-42%].

Sixteen patients with 2 pathogenic *MEFV* variants displayed IL-18 levels >7000 pg/mL in 25 visits (8.8%). These patients were significantly less frequently treated with colchicine (70.8% vs 98.7%, P < .001). Moreover, the colchicine dose was significantly lower in these visits (1 vs 1.5 mg/d, P = .033). Finally, colchicine was imperfectly or not taken in 13 of the 25 visits (52%).

Overall, we found that IL-18 levels in patients with FMF were elevated in a gene-dose-dependent manner but did not reliably reflect disease activity. Furthermore, IL-1 blocker use was not associated with a decrease in IL-18 levels, suggesting that they do not directly treat inflammasome dysregulation. The persistence of elevated IL-18 in asymptomatic patients with FMF could suggest low-level inflammasome activation even when FMF is clinically inactive, indicating subclinical inflammation. High IL-18 levels could be a marker of undertreatment, particularly in patients noncompliant with colchicine, which is essential to prevent AA amyloidosis. However, because elevated SAA is required for the development of AA amyloidosis, the clinical relevance of high IL-18 levels in clinically inactive patients with normal CRP and SAA remains to be established.
Limitations of this study include the retrospective design and the reliance on physician assessments for disease activity, which may be subjective. Moreover, most patients had only a single IL-18 measurement, limiting analysis of IL-18 variability over time or in response to treatments.

In conclusion, the role of IL-18 in FMF monitoring is not yet clear. Unlike CRP and SAA, serum IL-18 levels do not appear to reflect the immediate inflammatory state of patients with FMF, potentially making it a longer-term inflammatory biomarker. However, its poor performance in detecting disease activity limits its use in clinical practice. Therefore, this study does not support the measurement of serum total IL-18 for monitoring disease activity in FMF, although it may provide insight into subclinical inflammation and treatment adherence.

## Acknowledgments

This research was supported by the teams in charge of the clinical data warehouse of greater Paris University Hospital (AP-HP).

Conflicts of Interest: The authors declare that they have no relevant conflicts of interest.

Received for publication November 7, 2024; revised November 18, 2024; accepted for publication November 27, 2024.

Available online December 10, 2024.

Corresponding author: Inès Elhani, MD, PhD, or Sophie Georgin-Lavialle, MD, PhD, Department of Internal Medicine, CEREMAIA (National reference center for autoinflammatory diseases ad AA amyloidosis), Tenon Hospital, Sorbonne University, AP-HP, 4 rue de la Chine, 75020 Paris, France. E-mail: ines.elhani@aphp.fr. Or Sophie.georgin-lavialle@aphp.fr.

2213-2198

© 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

https://doi.org/10.1016/j.jaip.2024.11.025

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4. Deveci K, Korkmaz S, Senel S, Deveci H, Sancakdar E, Uslu AU, et al. Do neutrophil gelatinase-associated lipocalin and interleukin-18 predict renal dysfunction in patients with familial Mediterranean fever and amyloidosis? Ren Fail 2014;36:339-44.

5. Haznedaroglu S, Oztürk MA, Sancak B, Goker B, Onat AM, Bukan N, et al. Serum interleukin 17 and interleukin 18 levels in familial Mediterranean fever. Clin Exp Rheumatol 2005;23(Suppl 38):S77-80.

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7. Wada T, Toma T, Miyazawa H, Koizumi E, Shirahashi T, Matsuda Y, et al. Longitudinal analysis of serum interleukin-18 in patients with familial Mediterranean fever carrying MEFV mutations in exon 10. Cytokine 2018;104:143-6.

8. Yamazaki T, Shigemura T, Kobayashi N, Honda K, Yazaki M, Masumoto J, et al. IL-18 serum concentration is markedly elevated in typical familial Mediterranean fever with M694I mutation and can distinguish it from atypical type. Mod Rheumatol 2016;26:315-7.

9. Georgin-Lavialle S, Savey L, Buob D, Bastard JP, Fellahi S, Karras A, et al. French practical guidelines for the diagnosis and management of AA amyloidosis. Rev Med Interne 2023;44:62-71.

10. Infevers - Tabular list [Internet]. Accessed January 13, 2025. https://infevers.umai-montpellier.fr/web/search.php?n=1

<footnote><sup>a</sup>Department of Internal Medicine, Tenon Hospital, DMU 3ID, Sorbonne Université—Assistance Publique Hôpitaux de Paris, Paris, France</footnote>

<footnote><sup>b</sup>CEREMAIA (National reference center for autoinflammatory diseases ad AA amyloidosis), Paris, France</footnote>

<footnote><sup>c</sup>Department of Biochemistry, Tenon Hospital, DMU BioGemH, Sorbonne Université—Assistance Publique Hôpitaux de Paris, Paris, France</footnote>

<footnote><sup>d</sup>INSERM, UMRS 1155 UPMC, hôpital Tenon, Paris, France</footnote>

<footnote><sup>e</sup>ERN RITA—European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases, Utrecht, Netherland</footnote>

<footnote><sup>f</sup>Pediatric Rheumatology Department, Kremlin Bicêtre Hospital, AP-HP, Le Kremlin Bicêtre, Paris Saclay University, Paris, France</footnote>

<footnote><sup>g</sup>Department of General Pediatrics, Armand Trousseau Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France</footnote>

<footnote><sup>h</sup>Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debre, AP-HP, Paris, France</footnote>

<footnote><sup>i</sup>Pediatric Immunology, Hematology and Rheumatology Department, Necker Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>j</sup>Department of Molecular Genetics and Cytogenomics, Rare and Auto Inflammatory Diseases Unit, CHU Montpellier, University of Montpellier, Montpellier, France</footnote>

<footnote><sup>k</sup>Genetic Department, Trousseau Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>l</sup>Genetic Department, Cochin Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>m</sup>Department of Pediatrics, Versailles Hospital, Le Chesnay, France</footnote>

<footnote><sup>n</sup>INSERM U938, Paris, France</footnote>

<footnote>No funding was received for this work.</footnote>
ONLINE REPOSITORY

<table><caption>TABLE E1. Demographics and clinical characteristics of the 208 patients included</caption><thead><tr><th>Characteristic</th><th>Value (n = 208)</th></tr></thead><tbody><tr><td>Women</td><td>110 (53)</td></tr><tr><td>Mutational status</td><td></td></tr><tr><td>Homozygous</td><td>140 (67)</td></tr><tr><td>Compound heterozygous</td><td>46 (22)</td></tr><tr><td>Heterozygous</td><td>22 (11)</td></tr><tr><td>Median serum total IL-18 (pg/mL)</td><td>922.25 [153.5-22,712]</td></tr><tr><td>Colchicine ever</td><td>207 (99)</td></tr><tr><td>IL-1 blockers ever</td><td>13 (6)</td></tr><tr><td>No. of IL-18 measurements/patient</td><td>1 [1-5]</td></tr><tr><td>Age on the measurement day (y)</td><td>41 [17-82]</td></tr><tr><td>Serum total IL-18 (pg/mL)</td><td>991.5 [150-30,031]</td></tr><tr><td>C-reactive protein (mg/L)</td><td>4.1 [4-292.8]</td></tr><tr><td>Serum amyloid (mg/L)</td><td>8.25 [5.99-1330]</td></tr><tr><td>Controlled disease</td><td>151 (49)</td></tr><tr><td>Colchicine treatment on the measurement day</td><td>283 (96)</td></tr><tr><td>Colchicine dosage (mg/d)</td><td>1.5 [0-3]</td></tr><tr><td>IL-1 blockers on the measurement day</td><td>75 (24)</td></tr></tbody></table>

Values are presented as median [range] for quantitative variables and n (%) for qualitative variables.

<figure><img src="image_6.png" /><figcaption>FIGURE E1. IL-18 levels according to treatment with IL-1 blockers in homozygous and compound heterozygous patients. IL-18 levels before and after treatment initiation in patients. NS, Not significant.</figcaption></figure>