Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study).

Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60-0.63], sensitive: 0.77 [0.76-0.78], and specific: 0.67 [0.61-0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.

IR (index of reactivity)-house dust mite sublingual immunotherapy liquid formulation for allergic rhinoconjunctivitis: Systematic review and meta-analysis of randomized and nonrandomized studies.

Background: Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. Objective: We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. Methods: For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Results: Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD = -0.56; 95% CI, -0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively. Conclusion: This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

A successful linkage of a named patient products of sublingual immunotherapy-dispensing registry to French healthcare insurance database (SNDS): methodological constitution of the EfficAPSI cohort.

BACKGROUND: The only causal treatment for allergic rhinitis (AR) is allergen immunotherapy (AIT) including personalized liquid sublingual AIT (SLIT). We present the methodology for establishing the EfficAPSI cohort to further evaluate the real-life effectiveness and use of SLIT liquid. RESEARCH DESIGN AND METHODS: The EfficAPSI cohort was constituted by deterministic linkage of Stallergenes Greer dispensing and nationwide French healthcare insurance system (SNDS) databases. Data from 2006 to 2018 were extracted. All patients who initiated Stallergenes Greer SLIT liquid between 2010 and 2013 were considered as exposed and those dispensed with AR symptomatic treatment only as control. To limit the impact of confounding, the models will be weighted using the inverse probability of treatment weighting (IPTW). RESULTS: A total of 445,574 patients were included; median age was 38 years; 59.1% were female. Exposed patients (n = 112,492) were significantly younger, more frequently males, and less likely to have comorbidities than controls (n = 333,082). After IPTW, patients' characteristics from both groups were similar. CONCLUSIONS: To date, the EfficAPSI cohort has the largest number of person-years of follow-up in the field of AIT. The completeness of the data allows to evaluate SLIT liquid effectiveness with rigorous methodology, leading to important insights on personalized medicine in real-life.

Deciphering Differential Behavior of Immune Responses as the Foundation for Precision Dosing in Allergen Immunotherapy.

Like in many fields of medicine, the concept of precision dosing has re-emerged in routine practice in allergology. Only one retrospective study on French physicians' practice has addressed this topic so far and generated preliminary data supporting dose adaptation, mainly based on experience, patient profile understanding and response to treatment. Both intrinsic and extrinsic factors shape the individual immune system response to allergen immunotherapy (AIT). Herein, we focus on key immune cells (i.e., dendritic cells, innate lymphoid cells, B and T cells, basophils and mast cells) involved in allergic disease and its resolution to further understand the effect of AIT on the phenotype, frequency or polarization of these cells. We strive to discriminate differences in immune responses between responders and non-responders to AIT, and discuss the eligibility of a non/low-responder subset for dose adaptation. A differential behavior in immune cells is clearly observed in responders, highlighting the importance of conducting clinical trials with large cohorts of well-characterized subjects to decipher the immune mechanism of AIT. We conclude that there is a need for designing new clinical and mechanistic studies to support the scientific rationale of dose adaptation in the interest of patients who do not properly respond to AIT.

The MaDo real-life study of dose adjustment of allergen immunotherapy liquid formulations in an indication of respiratory allergic disease: Reasons, practices, and outcomes.

Sublingual allergen immunotherapy (SLIT) is a safe, effective, disease-modifying treatment for moderate-to-severe respiratory allergies. The function and responsiveness of the immune system components underlying the effects of allergen immunotherapy may vary from one patient to another. Furthermore, the severity of the symptoms of allergic disease can fluctuate over time, due to changes in environmental allergen exposure, effector cell responsiveness, and cell signaling. Hence, the allergen dose provided through SLIT can be fine-tuned to establish an optimal balance between effectiveness and tolerability. The objective of the MaDo study was to describe and understand dose adjustments of SLIT liquid formulations in France. We performed a retrospective, observational, cross-sectional, real-life study of allergists and other specialist physicians. Physicians described their patients via an anonymous case report form (CRF). The main patient inclusion criteria were age 5 years or over, at least one physician-confirmed IgE-driven respiratory allergy, and treatment for at least 2 years with one or more SLIT liquid preparations. A nationally representative sample of 33 specialist physicians participated in the study. The physicians' main stated reasons for dose adjustment were adverse events (according to 90.9% of the physicians), treatment effectiveness (60.6%), sensitivity to the allergen (42.4%) and other characteristics (30.3%: mainly symptom severity, type of allergen, and asthma). 392 CRFs (mean ± standard deviation patient age: 27.8 ± 17.5; under-18s: 42.1%; polyallergy: 30.9%) were analyzed. Respectively 53.6%, 25.8%, 15.3%, and 8.7% of the patients received house dust mite, grass pollen, birch pollen and cypress pollen SLIT. Dose adjustments were noted in 258 (65.8%) patients (at the start of the maintenance phase for 101 patients (39.2%) and later for 247 (95.7%)). Dose adjustment was not linked to sex, age, or the number of allergens administered. All measures of disease severity (including symptom severity noted on a 0-to-10 visual analogue scale by the physician) decreased significantly during SLIT. Notably, the mean AR symptom severity score decreased to a clinically relevant extent from 7.6 at SLIT initiation to 2.4 at last follow-up, and the mean asthma symptom severity score decreased from 5.0 to 1.3. The few differences in effectiveness between patients with vs. without dose adjustment were not major. For about one patient in five, a specialist physician decided to reduce or increase the SLIT liquid dose at the start of maintenance treatment and/or during maintenance treatment. This decision was influenced by a broad range of patient and treatment factors, mainly to improve tolerability to treatment and/or enhance effectiveness. In France, dose adjustment of SLIT liquid preparations as a function of the patient profile and/or treatment response is anchored in clinical practice. Precision dosing might optimize the overall benefit-risk profile of AIT for individual patients throughout their entire treatment course, enabling them to achieve both short- and long-term treatment goals, whilst maximizing the safety and tolerability.

Personalized medicine and allergen immunotherapy: the beginning of a new era?

The concept of personalized medicine as a diagnostic and therapeutic approach tailored to the medical needs of each patient is currently revolutionizing all fields of medicine and in particular allergology. Allergen immunotherapy (AIT) meets the three main needs for precision medicine: identification of molecular mechanism of disease, diagnostic tools for the mechanism and treatment blocking the mechanism itself. AIT adapts to the spectrum of specific IgE of each individual subject, changing the course and natural history of the disease, so is a clear model of precision and personalized medicine. This first step before the prescription of AIT is to define the sensitization profile of the patient; after that, the healthcare professional has numerous levers for adapting the treatment to the physio-pathological mechanisms involved. AIT allows to adapt treatments to the profile of the patients, but also to the its preferences, to ensure optimal treatment efficacy, resulting in an agile and personalized approach, with the aim to ensure adherence to the treatment, which is usually quite low. AIT also broadens the field of possibilities for healthcare professionals and patients, by allowing to choose the galenic formulation according to patient preferences and on the basis of their clinical history, adapting the product composition to the patient's sensitization profiles and the underlying biological mechanisms identified at the diagnostic stage, while guaranteeing quality of the prescribed product as the production of allergens and allergoids is today more regulated than in the past years. In the management of AIT, it is also possible to involve patients in decisions throughout their care pathway thanks to multiple services, offering personalized follow-up and support, to ensure the highest treatment efficacy levels, and recalling medication intake, medical appointments and prescription renewals.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Requirements for acquiring a high-quality house dust mite extract for allergen immunotherapy.

The house dust mite is a major cause of respiratory allergy worldwide. The management of mite allergy is based on avoidance measures, drug treatment, and allergen immunotherapy, but only allergen immunotherapy is able to modify the natural history of the disease. Injectable subcutaneous immunotherapy was introduced a century ago, while sublingual immunotherapy was proposed in the 1980s and emerged in the ensuing years as an effective and safe option to subcutaneous immunotherapy. However, the quality of the extracts to be used in allergen immunotherapy is crucial for the success of treatment. The mite extract for sublingual immunotherapy known as Staloral 300 was developed to offer optimal characteristics concerning the mite culture medium, standardization, and allergen dose. Double-blind, placebo-controlled trials with Staloral 300 have provided a substantial part of the clinical evidence analyzed in a meta-analysis of the efficacy of allergen immunotherapy in mite-induced rhinitis and asthma. Safety and tolerability are very good, mild local reactions in the mouth being the most common side effect. This makes it feasible to carry out sublingual immunotherapy for the 3-5-year duration needed to achieve long-lasting tolerance to the specific allergen. The performance of Staloral 300 may provide optimal conditions for an effective and safe sublingual immunotherapy in patients with mite-induced respiratory allergy.

Idiopathic eosinophilic parotitis in an eight-year-old boy: a case report.

INTRODUCTION: A number of medical conditions, some of them recently reported, are associated with an increased production of eosinophils. We report the first case of eosinophilic parotitis in the literature. CASE PRESENTATION: The patient was an eight-year-old Caucasian boy who presented with a two-year history of recurring acute parotitis with no fever. He had had a total of five episodes with no response to antibiotics, but remission had been achieved with oral corticosteroid therapy. We performed allergy tests for inhalant and food allergens and for haptens, but the results were all negative. The results of echography ruled out sialodochitis. Instead, a swab from the parotid duct led to the detection of a high number of eosinophils. CONCLUSIONS: This report is first in the literature to describe a case of eosinophilic parotitis, and we suggest that a cytological assessment, which is quite simple yet rarely used by physicians, be performed when patients with parotitis of uncertain origin are under evaluation.

The current role of sublingual immunotherapy in the treatment of allergic rhinitis in adults and children.

Allergic rhinitis is a very common disease affecting about 20% of people. It may be treated by allergen avoidance when possible, by antiallergic drugs such as antihistamines and topical corticosteroids, and by allergen-specific immunotherapy. The latter is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy and is able to maintain its efficacy even after stopping, provided an adequate duration of treatment of 3-5 years is ensured. Sublingual immunotherapy (SLIT) was introduced in the 1990s as a possible solution to the problem of adverse systemic reactions to subcutaneous immunotherapy and has been demonstrated by more than 50 trials and globally evaluated thus far by five meta-analyses as an effective and safe treatment for allergic rhinitis. Life-threatening reactions are extremely rare. However, it is important to note that clinical efficacy occurs only if SLIT meets its needs, ie, sufficiently high doses are regularly administered for at least 3 consecutive years. This is often overlooked in the current practice and may prevent the same success reported by trials from being achieved.

Polysensitization as a challenge for the allergist: the suggestions provided by the Polysensitization Impact on Allergen Immunotherapy studies.

INTRODUCTION: Polysensitization, that is, sensitization to more than one allergen family, is a common feature of patients with allergic rhinitis (AR) and significantly impairs their quality of life (QoL). Allergen-specific immunotherapy is the only causal treatment for AR. However, the polysensitization phenomenon may represent a crucial obstacle as far as it concerns the choice of the allergen extract to be used for immunotherapy. AREAS COVERED: A series of real-life based multi-center studies, named POLISMAIL (Polysensitization Impact on Allergen Immunotherapy), have been designed with the aim of evaluating the behavior of allergists in managing polysensitized AR patients. The effect of immunotherapy treatment in these patients was also evaluated. A single allergen extract was used in two-thirds of patients, whereas a mix of two allergens was chosen in the remaining. The severity grade of AR and the QoL were significantly improved by immunotherapy. Both outcomes confirmed that immunotherapy with one or two allergen extracts achieves a significant improvement in polysensitized patients. EXPERT OPINION: In conclusion, POLISMAIL studies demonstrate that polysensitization should not represent a counter-indication for prescribing immunotherapy. The choice of limiting sublingual immunotherapy to one to two allergen extracts, preferably separated and at high dosages, is sufficient and effective in improving symptoms and QoL.

Patient-related factors in rhinitis and asthma: the satisfaction with allergy treatment survey.

BACKGROUND: Patient satisfaction with the prescribed treatments represents a crucial issue that may have clinical relevance as it may significantly affect treatment compliance. We designed an observational study to evaluate the satisfaction level concerning different pharmacological treatments for allergic rhinitis (AR) and asthma in a real-life setting. METHODS: The study was conducted in 21 allergy centres homogeneously distributed in Italy. Three hundred and one patients (46.8% males; 53.2% females; mean [SD] age, 33.1 [13.8] years) with AR and/or asthma were consecutively evaluated. Diagnosis, classification, symptom severity, and satisfaction degree (assessed by a questionnaire) were the parameters considered. RESULTS: Only 33.5% of the AR patients were satisfied with the rhinitis treatments. Only 40.7% of the asthmatic patients were satisfied with the asthma treatments. Some factors associated with treatment dissatisfaction are as follows: female gender (odds ratio [OR] 2.36; p < 0.01), co-morbidity (OR 2.39; p < 0.05), rhinitis severity (OR 1.39; p < 0.05), asthma severity (OR 2.04; p < 0.05), and antihistamine use (OR 2.53); however, the use of bronchodilators had a favourable impact (OR 0.28; p < 0.05). The relatively low number of subjects prevented performing stratification of patients by treatment classes. CONCLUSION: The findings of this real-life study strengthen the concept that AR is particularly troublesome and that most allergic patients suffering from both rhinitis and asthma are dissatisfied with prescribed drugs.

Specific immunotherapy by the sublingual route for respiratory allergy.

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes.

Development of a sublingual allergy vaccine for grass pollinosis.

Grass pollen is a very common cause of allergic rhinitis and asthma. The only treatment targeting the underlying causes of allergy is immunotherapy (IT). Sublingual immunotherapy (SLIT) has been introduced to solve the problem of systemic reactions to subcutaneous IT (SCIT). This article evaluates the characteristics of the allergen extract, Staloral, in terms of practical administration, effectiveness, safety, and mechanism of action. Efficacy data were obtained from double-blind, placebo-controlled studies using Staloral in patients sensitized to grass pollen, while practical administration, cost-effectiveness, and mechanism of action data were provided by well designed studies. The efficacy and safety of Staloral, as demonstrated by review of published studies which used doses up to 1125 times those administered with SCIT, shows that this allergen extract has optimal characteristics for treating patients with seasonal allergies due to grass pollens. The main mechanism of action is the interaction between dendritic cells of the oral mucosa and the subsequent tolerance induced in T-cells.

Adherence issues related to sublingual immunotherapy as perceived by allergists.

OBJECTIVES: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. METHODS: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. RESULTS: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. CONCLUSION: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers.

Sublingual immunotherapy in children with allergic polysensitization.

Polysensitization is quite frequent in allergic children and may cause difficulties for the allergist in prescribing allergen-specific immunotherapy. This study aimed at evaluating the clinical effectiveness of 1 year of sublingual immunotherapy (SLIT) in a cohort of Italian allergic children with polysensitization. This open study was performed on 51 polysensitized children (34 boys; mean age, 11.8 years; range, 5.2-17.7 years) with allergic rhinitis and/or mild to moderate asthma. All of them were treated with SLIT for 1 year. The kind and the number of prescribed allergen extracts, the type of diagnosis, the severity of symptoms, and the use of drugs were evaluated at baseline and after 1 year. The adverse events to SLIT were also evaluated. Forty-two children were treated with a single extract, four with two different extracts and three with a mix of allergens. SLIT treatment induced a significant reduction in the number of sensitizations (p = 0.018); significant improvement of allergic rhinitis classification and severity; significant reduction of ocular, nasal, and bronchial symptoms (p < 0.01 for all); and drugs use (p < 0.01 for all drugs). No systemic reactions to SLIT were observed. This open study provides evidence that polysensitization is not an obstacle for prescribing SLIT in polysensitized children. Indeed, SLIT efficacy on clinical parameters is significant after 1 year and the therapy is safe.

Development of an allergen extract for sublingual immunotherapy--evaluation of Staloral.

BACKGROUND: Specific immunotherapy (IT) is an effective treatment for rhinitis and asthma caused by aeroallergens sensitization. Sublingual IT (SLIT) was introduced to solve the problem of systemic reactions to subcutaneous IT (SCIT) and developed to represent an actual treatment option. It is now generally accepted that allergen doses much higher than those administered by SCIT must be used to achieve clinical efficacy on allergic symptoms. OBJECTIVE: To evaluate the characteristics of Staloral, an allergen extract produced by Stallergenes (Antony, France) in terms of practical administration, efficacy, safety and mechanism of action. METHODS: Data were obtained from 20 double-blind, placebo-controlled studies using Staloral in patients sensitized to pollens and house-dust mites, and also from open studies concerning practical administration and the mechanism of action. RESULTS/CONCLUSION: Efficacy and safety of Staloral, as demonstrated by the revision of the studies, which used doses up to 1125 times those administered with SCIT, are very satisfactory and confer to this allergen extract optimal characteristics for treating patients with seasonal allergies due to pollens or with perennial symptoms induced by dust mites. The main mechanism of action is the interaction with dendritic cells of the oral mucosa and the subsequent tolerance induced in T cells.

Effects of sublingual immunotherapy on allergic inflammation.

The clinical expression of the most common allergic diseases reflects allergic inflammation and underlines that inflammation is the main target of anti-allergic therapies. Allergen specific immunotherapy (AIT) has a recognized impact on allergic inflammation, which persists after its discontinuation, and is the only therapy able to modify the natural history of allergic march. The traditional, subcutaneous route of administration is effective in altering the phenotype of allergen-specific T cells, switching from a Th2-type response, characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy or tolerance of Th2, the latter related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual IT with high allergen doses proved to be similar compared to subcutaneous immunotherapy. Recent data obtained in biopsies clearly indicate that the pathophysiology of the oral mucosa, and in particular mucosal dendritic cells, plays a pivotal role in inducing tolerance to the administered allergen.

Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms.

Antiphospholipid antibodies (Abs) are associated with thrombosis and are a risk factor for recurrent pregnancy loss and obstetric complications in patients with the antiphospholipid syndrome. It is generally accepted that the major autoantigen for aPL Abs is beta (2) glycoprotein I, which mediates the binding of aPL Abs to target cells (i.e., endothelial cells, monocytes, platelets, trophoblasts, etc.) leading to thrombosis and fetal loss. This article addresses molecular events triggered by aPL Abs on endothelial cells, platelets, and monocytes and complement activation, as well as a review of the current knowledge with regard to the putative receptor(s) recognized by aPL Abs on target cells as well as novel mechanisms that involve fibrinolytic processes. A section is devoted to the description of thrombotic and inflammatory processes that lead to obstetric complications mediated by aPL Abs. Based on experimental evidence using in vitro and in vivo models, new targeted therapies for treatment and/or prevention of thrombosis and pregnancy loss in antiphospholipid syndrome are proposed.