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OBJECTIVES: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a non-Mendelian autoinflammatory disorder until now considered to be specifically limited to paediatric age. Recently, an increasing number of reports seems to suggest that PFAPA syndrome, diagnosed by the Marshall criteria revised by Thomas et al., can also affect adults. METHODS: The Marshall/Thomas criteria have been applied to 989 adult patients presenting for recurrent fever episodes: all patients enrolled were reviewed for demographic, clinical, and therapeutic data. Infectious, neoplastic, autoimmune and other autoinflammatory diseases were ruled out. RESULTS: We identified 30 adult patients (19 males, 11 females) with a suspected PFAPA syndrome: their mean age at disease onset was 33.75±14.01 years, mean age at diagnosis 39.1±14.39 years, and mean body temperature peak 39.5±0.7°C. In addition, the mean frequency of febrile episodes was 11.58±8.97 per year. More precisely, patients complained of pharyngitis (77%), cervical adenitis (73%), asthenia (63%), arthralgia (67%), oral aphthosis (50%), myalgia (54%), cephalalgia (43%), abdominal pain (27%), nausea/vomiting (17%), periorbital pain (17%), and arthritis (10%). Six out of 30 (20%) patients had suffered from PFAPA syndrome also during childhood, and the disease had reappeared in adulthood. CONCLUSIONS: We provide the largest monocentric cohort of patients diagnosed with a suspected PFAPA syndrome in adulthood confirming that this syndrome can occur also during adulthood; moreover, due to the medical history of our patients and based on our experience, PFAPA syndrome might relapse during adulthood after a temporary remission reached in the course of paediatric age.

Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs.

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors

INTRODUCTION: Behçet's syndrome (BS) is a systemic inflammatory disorder characterized by a wide range of potential clinical manifestations with no gold-standard therapy. However, the recent classification of BS at a crossroads between autoimmune and autoinflammatory syndromes has paved the way to new further therapeutic opportunities in addition to anti-tumor necrosis factor agents. AREAS COVERED: This review provides a digest of all current experience and evidence about pharmacological agents recently described as having a role in the treatment of BS, including interleukin (IL)-1 inhibitors, tocilizumab, rituximab, alemtuzumab, ustekinumab, interferon-alpha-2a, and apremilast. EXPERT OPINION: IL-1 inhibitors currently represent the most studied agents among the latest treatment options for BS, proving to be effective, safe and with an acceptable retention on treatment. However, since BS is a peculiar disorder with clinical features responding to certain treatments that in turn can worsen other manifestations, identifying new treatment options for patients unresponsive to the current drug armamentarium is of great relevance. A number of agents have been studied in the last decade showing changing fortunes in some cases and promising results in others. The latter will potentially provide their contribution for better clinical management of BS, improving patients' quality of life and long-term outcome.

Paroxysmal crises of fever and systemic inflammation herald familial Mediterranean fever (FMF), considered as the archetype of all inherited systemic autoinflammatory diseases. Inflammatory bouts are characterized by short-term and self-limited abdominal, thoracic, and/or articular symptoms which subside spontaneously. Erysipelas-like findings, orchitis, and different patterns of myalgia may appear in a minority of patients. In recent years, many non-classical manifestations have been reported in the clinical context of FMF, such as vasculitides and thrombotic manifestations, neurologic and sensory organ abnormalities, gastrointestinal diseases, and even macrophage activation syndrome. As FMF left unrecognized and untreated is ominously complicated by the occurrence of AA-amyloidosis, it is highly desirable that diagnosis of this autoinflammatory disorder with its multiple clinical faces can be contemplated at whatever age and brought forward.

A peculiar coexistence of axial spondyloarthritis and ischemia of the feet and the fourth finger of the left hand in a young woman, who was a heavy smoker, is discussed in this report. This picture was considered within the context of thromboangiitis obliterans. Positivity of anti-nuclear antibodies and mild elevation of inflammatory parameters were noted. Computed tomography angiograms of upper and lower limbs showed luminal narrowing and occlusion of the left humeral, left anterior/posterior tibial and right anterior tibial arteries. Daily iloprost perfusions were started, and smoking cessation was strongly recommended. Coldness and rest pain in the distal extremities improved within a few weeks. The possibility that spondyloarthritis might precede the clinical picture of thromboangiitis obliterans should be considered in heavy smokers.

A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet's disease, gout, Sjögren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

Autoinflammatory and autoimmune disorders are characterized by chronic activation of the immune system, which leads to systemic self-directed inflammation in genetically predisposed individuals. Mutations in inflammasome-related proteins have been associated with autoinflammatory disorders, and the link between inflammasome and autoimmune disorders is becoming increasingly clear. As researchers learn more about these two areas, other disorders that were once thought to be autoimmune are now being considered autoinflammatory, or as having at least an autoinflammatory component. This review depicts the role of interleukin-1 as "Ariadne's thread" on the path through the labyrinth of autoinflammatory and autoimmune disorders and emphasizes the blurred boundary between innate and adaptive immune systems.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is the most common autosomal dominant autoinflammatory disease, resulting from mutations in the TNFRSF1A gene, encoding the 55-kD tumor necrosis factor receptor. The pathophysiologic mechanism of TRAPS remains ambiguous and only partially explained. The onset age of the syndrome is variable and the clinical scenery is characterized by recurrent episodes of high-grade fever that typically lasts 1-3 weeks, associated with migrating myalgia, pseudocellulitis, diffuse abdominal pain, appendicitis-like findings, ocular inflammatory signs, and risk of long-term amyloidosis. Fever episodes are responsive to high-dose corticosteroids, but different classes of drugs have been reported to be ineffective. The use of etanercept is unable to control systemic inflammation, while interleukin-1 blockade has been shown as effective in the control of disease activity in many patients reported so far.