Management of allergy transfer upon solid organ transplantation.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor-Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut-specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living-donor kidney recipients. All pollen-specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor-derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid-organ transplantation from donors with a history of fatal anaphylaxis.

[Allergy to furry animals: myth and reality]. / Allergies aux animaux à poils†: mythes et réalités.

Allergy to furry animals is a frequent health issue, and should be suspected when investigating any yearlong rhinoconjonctivitis or asthma. A detailed medical history and skin prick tests are usually sufficient for diagnosis, and if necessary, specific IgE testing may be performed. In case of proven hypersensitivity, avoidance of animal allergens is the main therapeutic measure, primarily by removing the animal from the patient's environment, in association with symptomatic treatment. If animal removing is impossible, other measures exist to decrease allergen load, but not with the same -efficacy as removing the animal, particularly for asthma. Immunotherapy is available for cat and dog allergy, but indication is to be carefully discussed.

Les allergies aux mammifères à poils sont une problématique ­répandue, et une hypersensibilité aux phanères d'animaux est à rechercher devant toute rhino-conjonctivite ou tout asthme ­perannuels. Une anamnèse soigneuse associée aux prick-tests permet d'orienter le diagnostic, qui sera en cas de doute complété par des dosages d'immunoglobulines E (IgE) spécifiques. Face à une hypersensibilité avérée, l'éviction est la pierre angulaire de la prise en charge, associée à un traitement symptomatique. En cas d'impossibilité pour le patient de se séparer de son animal, des mesures existent pour diminuer la charge en allergènes, bien qu'elles soient insuffisantes pour prévenir toute ­exacerbation des symptômes, surtout en cas d'asthme. Des ­désensibilisations existent pour l'allergie au chat et au chien, à discuter au cas par cas.

New therapeutic perspectives to manage refractory immune checkpoint-related toxicities.

Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.

The Candidate Blood-stage Malaria Vaccine P27A Induces a Robust Humoral Response in a Fast Track to the Field Phase 1 Trial in Exposed and Nonexposed Volunteers.

Background: P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults. Methods: This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 µg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 µg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up. Results: Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects. Conclusions: The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials. Clinical Trials Registration: NCT01949909, PACTR201310000683408.

Novel Nanofluidic IgE Assay versus a Reference Method: A Real-World Comparison.

BACKGROUND: Clinically meaningful specific IgE determination is an important step in the diagnosis of allergic diseases. While patient's history and skin prick tests are available during the medical visit, most IgE immunoassays require hours to several days to be available. Recent developments in the field of nanofluidic technology open new horizons for point-of-care management of this unmet medical need. OBJECTIVE: This study aimed to compare IgE diagnostic agreement between a nanofluidic assay (abioSCOPE®) and a laboratory reference method (Phadia Laboratory System®) in a real-world clinical setting. METHODS: Sera from 105 patients whose routine allergy diagnostic workup required a blood sampling were used to compare the novel nanofluidic IgE assay to a reference method in a blind manner for a panel of five respiratory allergens. To assess the agreement between methods, patient records were reviewed by four independent experts to establish the final diagnosis. Experts were blinded to the IgE serological method used, but had access to patient history, skin prick tests, and blood test results. RESULTS: Analytic agreement between the two methods was 81% for the tested panel of allergens (ranging from 77 to 89%). The overall agreement in clinical diagnosis decision taken by the expert panel was 94.6% with the nanofluidic IgE assay when compared to the reference method. CONCLUSION: The nanofluidic IgE assay, as determined through an evaluation based on clinical history, skin prick tests, and IgE measurement, is a valuable tool for allergy experts to identify patients' sensitization patterns at the point of care, and for routine IgE diagnostic workup.

[Where are we with oral immunotherapy for food allergy ?] / Allergologie-immunologie: Où en est-on avec l'immunothérapie orale dans l'allergie alimentaire ?

In allergology, food allergy is probably the problem to which medicine has brought the least therapeutic response so far. While oral immunotherapy for peanut, egg and milk is reserved for a few special cases and is not routinely recommended, apple desensitization for adult oral syndrome seems to bring some benefits in clinical practice, particularly in patients with restricted diet in fruits.

Dans le domaine de l'allergologie, l'allergie alimentaire est probablement la problématique à laquelle la médecine a apporté le moins de réponses thérapeutiques jusqu'ici. Alors que l'immunothérapie orale pour les cacahouètes, l'œuf et le lait est réservée à quelques cas particuliers et n'est pas recommandée de routine, la désensibilisation à la pomme lors de syndrome oral croisé chez l'adulte semble apporter certains bénéfices en pratique clinique, en particulier pour des patients dont le régime alimentaire en fruits est considérablement réduit.

[Risk of treatment failure and therapeutic novelties in asthma]. / Allergologie-immunologie: Facteurs d'échec du traitement de l'asthme et nouveautés thérapeutiques.

Asthma is a chronic disease that is still frequently poorly controlled, despite recent advances in understanding its pathophysiology. Poor compliance and ineffective inhalation technique remain the main causes of treatment failure. The comorbidities associated with asthma, such as obesity and chronic rhinosinusitis, are other elements to consider in the management of patients. Biological treatments targeting inflammation mediators show encouraging results in recurrent asthma exacerbations despite optimal management. However, their benefit remains limited to certain patients, thus requiring the study of predictive biomarkers to better delineate their indication.

L'asthme est une maladie chronique encore souvent mal contrôlée, et ce, malgré les récents progrès concernant la compréhension de sa physiopathologie. Une mauvaise adhésion aux traitements et une technique d'inhalation inefficace restent les causes principales d'échecs thérapeutiques. Les comorbidités associées à l'asthme, telles que l'obésité et la rhinosinusite chronique, sont d'autres éléments à considérer dans la prise en charge des patients. Lors d'exacerbations asthmatiques récidivantes, malgré une prise en charge optimale, des traitements biologiques ciblant les promoteurs de l'inflammation montrent des résultats encourageants. Leur bénéfice reste toutefois limité à certains patients, ce qui impose à l'avenir l'étude de biomarqueurs prédictifs de réponse à ces traitements ciblés.

Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease.

OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. METHODS: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. RESULTS: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. CONCLUSIONS: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. TRIAL REGISTRATION NUMBER: NCT02398435.

[Sublingual immunotherapy for the treatment of allergic rhinoconjonctivitis and asthma : a practical approach]. / Immunothérapie sublinguale pourle traitement de la rhinoconjonctivite et l'asthme allergique : guide pratique.

The prevalence of allergic diseases has been increasing over the past 50 years, leading to social and economic consequences. Immunotherapy is the only disease-modifying therapy available for allergic diseases, with durable long-term benefits. Immunotherapy is primarily available in two forms : 1) subcutaneous injections or 2) sublingual tablets/drops. The latter offers the advantage of being managed by the patient himself, requires no injections and has a far lower risk of severe systemic adverse events. In Switzerland, the use of sublingual immunotherapy is still scarce. This article reviews the indications, the administration technics and the contraindications to sublingual immunotherapy.

La prévalence des maladies allergiques est en augmentation ces 50 dernières années et implique des répercussions sur le plan socio-économique. Au contraire des traitements pharmacologiques habituels, l'immunothérapie spécifique de l'allergène offre la perspective de moduler le cours de la maladie avec un effet durable suite à l'arrêt du traitement. Elle est principalement administrée sous deux formes : 1) injection sous-cutanée et 2) sublinguale. Cette dernière technique présente l'avantage d'une prise à domicile par le patient et s'associe à un taux de réactions systémiques faibles et limitées en sévérité. En Suisse, l'usage de l'immunothérapie sublinguale est encore peu fréquent. Cet article a pour objectif de faire le point sur les indications, les techniques d'administration et les contre-indications à l'immunothérapie sublinguale.

[Seasonal allergic rhinitis]. / Rhinite allergique saisonnière.

Allergic diseases are currently amongst the most frequent diseases of our time. Of all the allergies in the Western countries, allergic rhinoconjunctivitis is the most common. Its diagnosis is based mainly on the history and the correlation between symptoms and contact with the allergen. A step-by-step approach helps optimize diagnostic resources and minimize costs.

Les allergies font partie des maladies les plus fréquentes de notre époque. Parmi toutes les allergies dans le monde occidental, la rhinoconjonctivite allergique est la plus fréquente. Son diagnostic repose principalement sur l'anamnèse et la corrélation entre symptômes et contacts avec l'allergène. Une démarche par étapes aide à optimiser les ressources diagnostiques et à minimiser les coûts.

Successful therapy with mycophenolic acid in a membranous glomerulonephritis due to Kimura disease
.

Kimura disease (KD) is a rare inflammatory soft tissue disorder of unknown origin most frequent in Asians, the prevalence of which is growing in Western countries. Painless papules and/or nodules with a predilection for the head and the neck region, lymphadenopathies, parotid gland involvement, eosinophilia, and raised IgE levels are parts of its presentation. Renal involvement with various forms of glomerulonephritis, including membranous nephropathy (MN), can occur and is generally associated with a proteinuria that encompasses nephrotic syndrome. Corticosteroids are the mainstay of treatment of KD-associated glomerulonephritis, but steroids withdrawal is often followed by relapsing nephrotic syndrome. Various immunosuppressive agents have been tested to prolong the remission of KD-associated nephrotic syndrome while tapering steroids, but they are only partly effective or associated with significant complications. To the best of our knowledge, we describe here the first case of KD-related membranous glomerulonephritis with a favorable evolution and a sustained remission of 4 years under prolonged therapy with mycophenolic acid (MPA). MPA and its active metabolite, mycophenolate mofetil (MMF), treatments as supportive therapies to corticosteroids and ACE inhibitors should be further investigated in KD-related membranous nephropathies.
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Efficacy of 2 months of allergen-specific immunotherapy with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: Results of a phase IIb study.

BACKGROUND: An immunotherapy formulation consisting of 3 contiguous overlapping peptides (COPs) derived from Bet v 1, the major birch pollen allergen, showed good clinical tolerability in a previous phase I/IIa clinical trial. OBJECTIVES: We sought to evaluate the efficacy and safety of allergen-specific immunotherapy using 2 dose regimens of Bet v 1 COPs versus placebo in subjects with birch pollen-induced allergic rhinoconjunctivitis. METHODS: A randomized, double-blind, placebo-controlled phase IIb clinical trial was performed to assess the efficacy of Bet v 1 COP immunotherapy during the 2013 birch pollen season. Before the season, Bet v 1 COPs (50 and 100 µg in aluminum hydroxide) or placebo (saline and aluminum hydroxide) were administered as 5 subcutaneous injections to 239 adults with allergic rhinoconjunctivitis to birch pollen. Bet v 1 COPs at 25 or 50 µg were administered on day 1, and 50 or 100 µg was administered on days 8, 15, 29, and 57, respectively. Patients were monitored for adverse events during the treatment period and assessed for combined rhinoconjunctivitis symptom and medication scores, as well as quality of life. RESULTS: Rhinoconjunctivitis symptom and medication scores improved in both Bet v 1 COP-treated groups, reaching statistical significance over placebo in the 50-µg group (least squares mean, -0.23; 26% improvement; P = .015). Both active groups showed significant improvement in quality of life and nighttime nasal symptom scores, supporting the primary end point findings. Bet v 1 COP injections were well tolerated, with a higher frequency of systemic adverse events in the 100-µg group. CONCLUSION: Two months of preseasonal immunotherapy with 3 COPs derived from Bet v 1 at a 50-µg dose showed promising efficacy, small risk for systemic reactions, and immunomodulatory changes in this single-season, dose-finding, phase IIb trial in patients allergic to birch pollen.

MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis.

The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials.

[Hope for chronic inflammatory diseases : the anti-IL-6 receptor monoclonal antibody tocilizumab]. / Allergologie-immunologie Clinique. De l'espoir pour les pathologies inflammatoires chroniques : l'antirécepteur de l'IL-6 tocilizumab.

Vasculitis like Horton's disease, some autoinflammatory syndromes (Behcet's, Still's diseases) often require long term treatment with steroids, and therefore are associated with non acceptable adverse events, especially when resistant to treatment. Recently, a number of controlled prospective clinical trials are supporting the interest of the anti-IL-6 receptor monoclonal antibody tocilizumab in these chronic inflammatory conditions et may soon be recognized as second intention therapeutic approach.

Certaines vasculites comme la maladie de Horton en particulier, certaines pathologies auto-inflammatoires (maladies de Behcet, de Still) imposent aux patients des traitements de longue durée par les stéroïdes et donc les exposent à des effets secondaires à long terme souvent inacceptables dans les formes résistantes. Depuis peu, quelques études contrôlées, prospectives sont venues soutenir l'intérêt de l'antirécepteur de l'IL-6 monoclonal dans ces pathologies, et laissent penser qu'il puisse prochainement devenir un traitement de seconde intention dans le Horton notamment.

[Innovations in the treatment of severe asthma]. / Allergologie-immunologie clinique. Nouveautés dans le traitement de l'asthme sévère.

In severe asthma, there is a real need for new effective therapies offering a good safety and tolerance profile. Mepolizumab is a humanized anti-interleukin-5 monoclonal antibody, available in Switzerland since 2016 for treatment of severe adult eosinophilic asthma. Other monoclonal antibodies, such as dupilumab, are being developed in the field of asthma.

Dans l'asthme sévère, il existe un réel besoin de nouvelles thérapies efficaces offrant de bons profils de sécurité et de tolérance. Le mépolizumab est un anticorps monoclonal humanisé dirigé contre l'interleukine 5, disponible en Suisse depuis 2016 pour le traitement de l'asthme éosinophilique sévère de l'adulte. D'autres anticorps monoclonaux, comme le dupilumab, un anti-IL-4R, sont actuellement en cours de développement dans cette indication.

[Food-dependent exercise-induced anaphylaxis : a stepwise diagnosis]. / Anaphylaxie alimentaire à l'effort : un diagnostic par étapes.

Food-dependent exercise-induced anaphylaxis (FDEIA) is a potentially severe food allergy. Physical exercise, NSAID, alcohol, infectious diseases and estrogens are recognized cofactors, able to reduce the amount of allergen needed to achieve a threshold for the induction of anaphylaxis. Various kinds of causative food but only a few responsible proteins have been identified. The best known is wheat ω5-gliadine. An oral food challenge remains the gold standard to prove the diagnosis. Its clinical application remains difficult and includes an allergen challenge, a cofactor challenge and a third step which integrates both of them in a single test. Gluten flour and NSAID + alcohol combination seem more efficient than respectively wheat flour and physical exercise in a provocation test condition.

L'anaphylaxie alimentaire à l'effort est une allergie alimentaire potentiellement sévère. L'exercice physique, les AINS, l'alcool, les infections et les œstrogènes sont des cofacteurs reconnus, capables de diminuer la quantité d'allergènes nécessaire à l'atteinte d'un seuil anaphylactique. Si le panel d'aliments incriminés est large, seules quelques protéines responsables ont été à ce jour identifiées. La plus connue est l'ω5-gliadine du blé. En cas d'incertitude diagnostique, un test de provocation est indiqué. Son application clinique reste difficile et inclut de tester l'allergène de manière isolée et le cofacteur puis d'intégrer les deux dans un même test. La farine de gluten et la combinaison AINS + alcool ont une sensibilité supérieure respectivement à la farine de blé et à l'exercice physique en situation de provocation.

Switching Patients to Home-Based Subcutaneous Immunoglobulin: an Economic Evaluation of an Interprofessional Drug Therapy Management Program.

PURPOSE: Home-based subcutaneous immunoglobulin (SCIg) therapy is an alternative to hospital-based intravenous infusions (IVIg). However, SCIg requires patient training and long-term support to ensure proper adherence, optimal efficacy and safety. We evaluated if switching patients to home-based SCIg including an interprofessional drug therapy management program (physician, community pharmacist and nurse) would be cost-effective within the Swiss healthcare system. METHODS: A 3-year cost-minimization analysis was performed from a societal perspective comparing monthly IVIg in an outpatient clinic and home-based weekly SCIg including an interprofessional program. Healthcare costs (immunoglobulin, professional time, infusion pump and disposables) were derived from administrative data. Transportation and productivity loss were estimated by expert opinion. The results were expressed in Swiss francs (CHF) and converted to Euros and US dollars (1 CHF = 0.92€, 1 CHF = $1.02; www.xe.com , 12/14/2015). RESULTS: Under base case assumptions, SCIg was estimated to cost 35,862 CHF (33,134€; $36,595) per patient during the first year and 30,309 CHF (28,004€; $30,929) in subsequent years versus 35,370 CHF (32,679€; $36,095) per year for IVIg. The total savings from switching to SCIg with the interprofessional program were 9630 CHF (8897€; $9828) per patient over 3 years. The results were relatively sensitive to the cost per gram of IgG, the cost of equipment and the annual number of infusions. CONCLUSION: Home-based SCIg including an interprofessional therapy management program may be an efficient alternative for patients. The program provides long-term support from self-administration training to the responsible use of therapy (proper adherence, optimal efficacy and safety). Over the short term, additional costs from purchasing equipment and the drug therapy management program were offset by avoiding hospital costs.

Interferon α kinoid induces neutralizing anti-interferon α antibodies that decrease the expression of interferon-induced and B cell activation associated transcripts: analysis of extended follow-up data from the interferon α kinoid phase I/II study.

OBJECTIVE: IFN α Kinoid (IFN-K) is a therapeutic vaccine composed of IFNα2b coupled to a carrier protein. In a phase I/II placebo-controlled trial, we observed that IFN-K significantly decreases the IFN gene signature in whole blood RNA samples from SLE patients. Here, we analysed extended follow-up data from IFN-K-treated patients, in order to evaluate persistence of neutralizing anti-IFNα Abs antibodies (Abs), and gene expression profiling. METHODS: Serum and whole blood RNA samples were obtained in IFN-K-treated patients included in the follow-up study, in order to determine binding and neutralizing anti-IFNα Ab titres, and perform high-throughput transcriptomic studies. RESULTS: Neutralization studies of 13 IFNα subtypes demonstrated the polyclonal nature of the Ab response induced by IFN-K. Follow-up analyses in six patients confirmed a significant correlation between neutralizing anti-IFNα Ab titres and decrease in IFN scores compared to baseline. These analyses also revealed an inhibitory effect of IFNα blockade on the expression of B cell associated transcripts. CONCLUSIONS: IFN-K induces a polyclonal anti-IFNα response that decreases IFN- and B cell-associated transcripts. TRIAL REGISTRATION: ClinicalTrials.gov, clinicaltrials.gov, NCT01058343.

Elevated serum levels of free interleukin-18 in adult-onset Still's disease.

OBJECTIVE: IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. METHODS: An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. RESULTS: Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. CONCLUSION: Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.