Silvia Federici

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients’ quality of life and prognosis.

The complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management.

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy‐related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper‐IgE syndromes, Omenn syndrome, Wiskott‐Aldrich syndrome, IPEX‐linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.

Background In the last years, an expanding group of complex genetic disorders characterized by disturbance of the homeostatic control of IFN-mediated immune responses, have been identified, so called type I interferonopathies. An increased expression of type I IFN regulated genes, IFN signature (IS), is described in these conditions. IS represent a useful tool in clinical practice to classify patients with suspected interferonopathies. Objectives To evaluate the correlation between clinical presentation, genetic analysis and IFN-score in 10 patients with undefined interpheronopathies Methods Patients with suspected interferonopathy based on the presence of typical clinical manifestations (neurological, muco-cutaneous symptoms), laboratory parameters (complement deficiency, low platelet count, presence of autoimmunity), instrumental abnormalities (cerebral calcification), were screened for the IFN-score. Defined IFN-mediated diseases were excluded. Patients presenting with a high IFN-score value (above a fixed cut-off of 10) underwent genetic screening by running a panel of 24 genes known to be involved in interferonopathies Results 10 patients with suspected interferonopathy followed in a single pediatric rheumatology center were included. 7/10 presented with recurrent episodes of fever (table). Patient 2, 3 and 7 displayed neurological manifestation, respectively epilepsy, epilepsy and mental retardation and progressive hemiplegia. To note epilepsy in patient 2 might be correlated to a bilateral intraventricular hemorrhage presented at birth. In two patients (1,4) gastrointestinal manifestation resembling inflammatory bowel diseases were described while patients 5,7 and 10 suffered from recurrent abdominal pain, diarrhea and patient 10 from hypertransaminasemia. Half of the patients complained arthromyalgia; arthritis developed in patient 2. Cutaneous involvement presented in 3 patients (1,3,6) respectively with a widespread panniculitis of trunk and limbs, aspecific vasculitis and Schonlein Henoch purpura. Other cutaneous manifestation were urticarial rash (pt 2) and an erythematous, desquamative confluent eczema (pt 4). Autoimmunity was confirmed in 2/10 patients. Two patients (4, 8) had an immunological defect with recurrent infections. The genetic analysis resulted negative in patients 1 and 7 and is still ongoing in patients 5, 6 and 8. Patients 2,3,4,9 and 10 carried one mutation in at least one IFN correlated gene not confirming the diagnosis. All patients presented an increased IS ranging from 14,2 to 172,5 Conclusion An elevated IFN-score represent a useful instrument in the clinical practice to classify patients with suspected interferonopathy. It may represent an important tool to select those patients to be genetically screened with a defined panel of interferonopathies correlated genes. In those patients in which the genetic analysis result negative, the presence of a positive IFN-score, confirming an activation of this inflammatory pathway, may guide the clinicians in the management of these patients and may support therapeutic decisions Disclosure of Interests Silvia Federici: None declared, Gian Marco Moneta: None declared, Chiara Passarelli: None declared, Claudia Bracaglia: None declared, Carmela Gerarda Luana Raffaele: None declared, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Antonella Insalaco: None declared

Objective.: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF.Methods.: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1.Results.: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor–associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF.Conclusion.: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

The Chronic Infantile Neurological Cutaneous and Articular (CINCA, or Neonatal-onset multisystem inflammatory disease NOMID) is a rare autoinflammatory disease identified in 1987 by Prieur et al., typically characterized by the triad of skin rash, arthropathy and central nervous system manifestations. It represents the most severe phenotype of the cryopyrin-associated periodic syndrome (CAPS). The syndrome is due to autosomal dominant gain of function mutations in NLRP3, which encodes a key component of the innate immunity that regulates the activation and secretion of interleukin (IL)-1β. From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose. The CNS manifestations include chronic aseptic meningitis leading to brain atrophy, mental delay and sensorineural hearing loss. Chronic polyarthritis and alteration of the growth cartilage also may be present. CINCA/NOMID diagnosis is made clinically, based on the presence of characteristic features. The detection of NLRP3 mutations is diagnostic in 65–70% of cases. Indeed, up to 40% of affected patients are negative for germline NLRP3 mutations and several subjects are carriers of somatic mosaicism. Due to the pivotal role of Cryopyrin in the control of Caspase-1 activation and the massive secretion of active IL-1β observed in cryopyrin-mutated individuals, anti-IL1 treatment represents the standard therapy. Prognosis of CINCA/NOMID syndrome has been changed by the availability of anti-IL1 drugs. Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.

In this paper we provide a critical digest of the recent literature on inherited autoinflammatory diseases. We reviewed all the articles published during the last 24 months on monogenic autoinflammatory diseases and selected the most relevant studies regarding the pathogenesis, clinical aspects and management of these conditions. In particular, we focused the attention on the more frequent conditions, familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and TNF-receptor associated periodic syndrome (TRAPS).

Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways deputed to the activation and secretion of the potent inflammatory cytokine interleukin (IL)-1β. It became clear that several mutifactorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of IL-1 blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multifactorial autoinflammatory diseases.