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Ocular involvement is frequent in the monogenic autoinflammatory disorders and generally occurs as spontaneously recurring inflammatory events at different ocular sites caused by the aberrant release of proinflammatory cytokines, mainly IL-1β. Over the past decade, we witnessed a significant growth of eye abnormalities associated with idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. The pathogenetic mechanisms of these disorders have shown the evidence of disrupted cytokine signaling, but the explanation for the heterogeneous ocular involvement remains to be elucidated. We herein review the monogenic autoinflammatory disorders affecting the eye, describing their main clinical features with specific regard to the ocular involvement, which can lead to decreased visual acuity and even blindness, if the primary disorder is undetected or left untreated.

Purpose: To evaluate the 10-year drug retention rate of infliximab (IFX) in Behcet’s disease (BD)-related uveitis, the effect of a concomitant use of disease modifying anti-rheumatic drugs (DMARDs) on drug survival and differences according to the lines of biologic treatment.Methods: Cumulative survival rates were studied using the Kaplan-Meier plot, while the Log-rank (Mantel-Cox) test was used to compare survival curves.Results: Forty patients (70 eyes) were eligible for analysis. The drug retention rates at 12-, 24-, 60- and 120-month follow-up were 89.03%, 86.16%, 75.66% and 47.11% respectively. No differences were identified according to the use of concomitant DMARDs (p = 0.20), while a statistically significant difference was observed in relation to the different lines of IFX treatment (p = 0.014). Visual acuity improved from baseline to the last follow-up visit (p = 0.047) and a corticosteroid-sparing effect was observed (p

The purpose of the present study was to describe our experience with the recombinant Fab' antibody fragment against TNF-α Certolizumab Pegol (CZP) in patients with Behçet's disease (BD) refractory to standardized therapies and previous biologic agents.Retrieved data including demographic characteristics, clinical manifestations, and previous treatments were collected in three different specialized Rheumatologic Units in Italy. In order to evaluate disease activity, the BD current activity form (BDCAF) has been used before starting CZP therapy and at each visit during treatment.Thirteen BD patients (mean age 42.6 ± 8.8 years) with a disease duration of 8.80 ± 6.9 years, underwent CZP treatment for 6.92 ± 3.52 months. Six patients (46.15%) experienced a worsening of symptoms after 4.16 ± 1.21 months, whereas a satisfactory response was achieved in seven patients (53.84%) who were still on CZP therapy at the last follow-up visit (after 9.28 ± 3.03 months of treatment). The mean decrease of BDCAF between the first and last visit was 0.308 ± 1.84 without reaching significant difference (mean 8.3 ± 1.3 and 8 ± 2.08, respectively; p= .51). During the whole study period, CZP was well tolerated in all patients except one who developed a generalized cutaneous reaction after the third administration.These results suggest that despite an improvement of clinical manifestations has been observed in more than half of the patients, it is not possible to draw firm conclusions about the effectiveness of CZP in BD and further studies with larger cohorts of patients are warranted. Whether the increase of CZP dosage may ensure a better clinical response remains an unsolved issue that needs to be considered.

Background Current information on the use of adalimumab (ADA) in the treatment of ocular Behcet9s disease (BD) is still based mainly on small series or case reports; nonetheless preliminary evidence is promising. Objectives The study aim was to evaluate the efficacy of ADA in a large series of BD-related uveitis. Methods We performed a multicenter retrospective observational study including 40 selected patients (66 eyes) receiving ADA. Clinical data were retrospectively analyzed at baseline, at 3 and 12 months of treatment. Primary end-point was: reduction of ocular inflammatory flares. Secondary end-points were: improvement of Best Corrected Visual Acuity (BCVA), reduction of macular thickness measured by optical coherence tomography (OCT), reduction in the occurrence of vasculitis assessed by fluorescein angiography (FA), evaluation of statistically significant differences between patients treated with ADA monotherapy and those undergoing ADA plus DMARDs and in patients firstly treated with ADA compared to patients previously administered with other biologics; ADA steroid sparing effect was also evaluated. Results During the first 12 months of ADA therapy the number of flares significantly decreased from 200 flares/100 patients/year to 8.5 flares/100 patients/year (p Conclusions ADA is highly effective and safe for the treatment of BD-related uveitis, providing a long-term control of ocular inflammation. Disclosure of Interest None declared

Background Methotrexate (MTX) is the first line drug suggested in the ACR/EULAR guidelines to treat the rheumatoid arthritis (RA) (1) and spondylarthritis (SpA). Although MTX efficacy is demonstrated by high levels of evidences, maximum benefit might require interventions even earlier. For this reason, it is suggested to identify the patients (pts) with symptom onset of less than 12 weeks, that is very early arthritis, to obtain better outcomes. Few data are available by the clinical practice on MTX monotherapy (MTXm) survival in very early or early arthritis pts. Objectives We aim to evaluate the presence of different outcomes in MTXm drug survival and MTX efficacy between Very Early arthritis (VEA) pts (less than 12 weeks from symptom onset) and Early arthritis (EA) pts (12–52 weeks from symptom onset), and between early RA pts and early SpA pts. Methods On 305 pts, we selected 219 pts (30 pts diagnosed as VEA (4,2 (4) weeks from symptom onset) and 155 pts as EA (25,7 (25) wks from symptom onset) in which MTXm could be started. The RA pts were 93 and SpA pts were 126. To assess the MTXm persistency the Kaplan-Meier survival curves analysis was performed and Cox regression analysis was used to assess clinical predictors of MTXm suspension. The results are expressed as mean±standard deviation or median (interquartile range). A p≤0.05 was set for statistically significant. Results No difference in MTXm survival was found between VEA pts 95,5 (36) wks and EA 92,5 (10) wks (p=0,38) (Fig.1a). We observed a significant difference in drug survival between early RA pts 63 (16) wks) and early SpA pts 112,7 (15,8) wks (p=0,001) (Fig.1b). In 55% early RA pts and in 45% early SpA pts the biotechnology drug needs to be added because of disease flare. In the remaining pts a low disease activity (DAS≤3,2) was observed. No adverse events were recorded in follow-up period. In early RA pts predictors of shorter MTXm survival were younger age at diagnosis (p=0,004), lower dose of MTX (p=0,032), earlier diagnosis from symptom onset (p=0,0001), higher titer of rheumatoid factor (p=0,037) and female gender (p=0,019). In early SpA pts the only predictor of shorter MTXm survival was younger age at diagnosis (p=0,0,37). Smoking, disease activity at diagnosis and BMI were not predictors of MTXm survival. Conclusions The MTXm survival is not influenced by VEA or EA diagnosis. The RA seems to be less responder to MTXm than SpA. It might be due to the difficult to capture the earliest phase of disease, as circulating antibodies might appear years before the onset of symptoms in RA, and biomarkers reflecting bone destruction are elevated before arthritis is present, as described in previous studies. In particular, might be pay attention to younger pts, female gender and pts with higher titer of rheumatoid factor as they seem to present a more resistant RA disease. A high dose of MTX and earlier interventions are suggested in RA to improve the clinical outcome of patients and the MTXm survival. References Smolen JS et. Al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492–509. Disclosure of Interest None declared

Objectives To evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behcet disease (BD)-related uveitis Methods multicenter retrospective observational study including 19 consecutive BD patients (31 affected eyes) receiving treatment with anti-IL-1 agents. Data were analyzed at baseline, at 3 and 12 months. Primary end-point: reduction of ocular inflammatory flares (OIF). Secondary end-points: improvement of Best Corrected Visual Acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-α inhibitors Results at 12 months OIF significantly decreased from 200/100 patients/year to 48.87/100 patients/year (p p p =0.001, respectively). OIF rate was significantly higher in patients co-administered with DMARDs (81.8/100 patients/year) than in patients undergoing IL-1 inhibitors as monotherapy (0.0/100 patients/year) ( p =0.03). No differences were identified on the basis of corticosteroid use and between patients administered with IL-1 inhibitors as first-line biologic approach or second-line. Steroid dosage was significantly decreased at 12-month visit compared to baseline ( p =0.02). Conclusions treatment with IL-1 inhibitors is effective in the management of BD-related uveitis and provides a long-term control of ocular inflammation in refractory and long-lasting cases. Disclosure of Interest None declared

Several pathogenetic studies have paved the way for a newer more rational therapeutic approach to non-infectious uveitis, and treatment of different forms of immune-driven uveitis has drastically evolved in recent years after the advent of biotechnological drugs. Tumor necrosis factor-α targeted therapies, the first-line recommended biologics in uveitis, have certainly led to remarkable results in patients with non-infectious uveitis. Nevertheless, the decision-making process turns out to be extremely difficult in anti-tumor necrosis factor or multidrug-resistant cases. Interleukin (IL)-6 holds a critical role in the pathogenic pathways of uveitis, due to its extended and protean range of effects. On this background, manipulation of IL-6 inflammatory cascade has unraveled encouraging outcomes. For instance, rising evidence has been achieved regarding the successful use of tocilizumab, the humanized monoclonal antibody targeted against the IL-6 receptor, in treating uveitis related to juvenile idiopathic arthritis or Behcet's disease. Similar findings have also been reported for uveitis associated with systemic disorders, such as rheumatoid arthritis or multicentric Castleman disease, but also for idiopathic uveitis, the rare birdshot chorioretinopathy, and even in cases complicated by macular edema. This work provides a digest of all current experiences and evidences concerning IL-6 blockade, as suggested by the medical literature, proving its potential role in the management of non-infectious uveitis.

The study aim was to evaluate the efficacy of adalimumab (ADA) in a large series of Behcet's disease (BD)-related uveitis. We performed a multicenter retrospective observational study including 40 selected patients (66 eyes) receiving ADA. Clinical data were retrospectively analyzed at baseline, at 3 and 12 months of treatment. Primary end point was reduction of ocular inflammatory flares. Secondary end points were improvement of best corrected visual acuity (BCVA), reduction of macular thickness measured by optical coherence tomography (OCT), reduction in the occurrence of vasculitis assessed by fluorescein angiography (FA), and evaluation of statistically significant differences between patients treated with ADA monotherapy and those undergoing ADA plus DMARDs and in patients firstly treated with ADA compared to patients previously administered with other biologics; ADA steroid sparing effect was also evaluated. During the first 12 months of ADA therapy, the number of flares significantly decreased from 200 flares/100 patients/year to 8.5 flares/100 patients/year (p

Behçet’s disease (BD) is a multi-systemic inflammatory disorder consisting of recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis; however, many other organs may be affected. Several pro-inflammatory cytokines, mainly derived from Th1 and Th17 lymphocytes, seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. On this basis, the primary aim of our study was to compare a core set of pro-inflammatory cytokines between patients with BD and healthy control (HC). The secondary goal was to evaluate potential correlations between these putative circulating biomarkers, the status of disease activity, and the specific organ involvement at the time of sample collection. Fifty-four serum samples were collected from 46 BD patients (17 males, 29 females, mean age 45.5 ± 11.3 years), and 19 HC (10 males, 9 females, mean age 43 ± 8.3 years). Twenty-five serum cytokines (APRIL/TNFS13, BAFF/TNFSF13B, sCD30/TNFRSF8, sCD163, Chitinase3-like1, gp130/sIL-6Rb, IFNb, sIL-6Ra, IL-10, IL-11, IL-19, IL-20, IL-26, IL-27 (p28), IL-28A/IFN-lambda2, IL-29/IFN-lambda1, IL-32, IL-34, IL-35, LIGHT/TNFSF-14, Pentraxin-3, sTNF-R1, sTNF-R2, TSLP, and TWEAK/TNFSF-12) were simultaneously quantified using a Bio-Rad cytokine bead arrays. Serum concentration of sTNF-R1 (p

Our aim was to retrospectively assess the role of golimumab as a treatment choice in patients with Behcet’s disease (BD). Seventeen patients diagnosed with BD according to the international criteria were consecutively enrolled; the BD Current Activity Form (BDCAF) was used to evaluate disease activity. After having collected clinical data from patients, statistical analysis was performed to identify differences between the start of therapy and last visit; significance was defined as p

Background. A dysfunction of pain processing at central and peripheral levels was reported in fibromyalgia (FM). We aimed to correlate laser evoked potentials (LEPs), Sympathetic Skin Response (SSR), and clinical features in FM patients. Methods. Fifty FM patients and 30 age-matched controls underwent LEPs and SSR by the right hand and foot. The clinical evaluation included FM disability (FIQ) and severity scores (WPI), anxiety (SAS) and depression (SDS) scales, and questionnaires for neuropathic pain (DN4). Results. The LEP P2 latency and amplitude and the SSR latency were increased in FM group. This latter feature was more evident in anxious patients. The LEPs habituation was reduced in FM patients and correlated to pain severity scores. In a significant number of patients (32%) with higher DN4 and FIQ scores, SSR or LEP responses were absent. Conclusions. LEPs and SSR might contribute to clarifying the peripheral and central nervous system involvement in FM patients.

The study objective was to evaluate the occurrence of sensorineural hearing loss (SNHL) in patients with Behcet's disease (BD), looking at potential correlations with specific demographic, clinical, and therapeutic features. Forty-four consecutive patients (15 males, 29 females) fulfilling the International Study Group (ISG) and/or the International Criteria for Behcet's Disease (ICBD) were enrolled. The endpoints of the study consisted in identifying a deflection of at least 25 dB on pure-tone audiometry and performing statistical analysis to evaluate demographic, clinical, or therapeutic differences between patients with and without SNHL. Our patients showed a mean age ± SD of 45.43 ± 14.05 years; a mean age at disease onset ± SD of 31.54 ± 15.53 years; a disease duration ± SD of 13.89 ± 9.15 years. SNHL was highlighted in 28 (63 %) patients representing the fourth most frequent clinical manifestation in our group of patients. Otologic involvement was significantly more frequent among subjects fulfilling ISG criteria than in patients fulfilling ICBD criteria (p = 0.04). Regarding correlations with BD manifestations, SNHL was significantly associated with cutaneous plus articular involvement (p = 0.013). Conversely, detached analysis of articular and skin manifestations led to no significant differences (p = 0.085 and p = 0.067). No further significant correlations were found between SNHL and BD clinical features or previous or concomitant treatments. Hearing loss was the fourth most common clinical feature in our patients and probably represents an underrated aspect of BD. Hearing impairment was significantly associated with cutaneous plus articular involvement, suggesting the importance of an otologic evaluation in such patients.

Behçet’s disease (BD) is a multisystemic disorder of unknown etiology mainly defined by recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis, all of which represent the “stigmata” of disease. However, many other organs including the vascular, neurological, musculoskeletal, and gastrointestinal systems can be affected. The gastrointestinal involvement in Behçet’s disease (GIBD), along with the neurological and vascular ones, represents the most feared clinical manifestation of BD and shares many symptoms with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. Consequently, the differential diagnosis is often a daunting task, albeit the presence of typical endoscopic and pathologic findings may be a valuable aid to the exact diagnosis. To date, there are no standardized medical treatments for GIBD; therefore therapy should be tailored to the single patient and based on the severity of the clinical features and their complications. This work provides a digest of all current experience and evidence about pharmacological agents suggested by the medical literature as having a potential role for managing the dreadful features of GIBD.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a mysterious disorder characterized by periodically recurrent fevers, oropharyngeal inflammation, and adenitis, which mainly affects children, though in very recent times, it has been also recognized in adulthood. We enrolled 115 unrelated pediatric and adult patients with history of periodic fevers who fulfilled the current diagnostic criteria for PFAPA syndrome in three Italian referral centers and highlighted differences between children and adults. Eighty-five children and 30 adults were evaluated: the frequency of flares was significantly higher in pediatric cases, while febrile attack duration was significantly longer in adults. Clockwork periodicity of fever and recurrent pharyngitis were more frequently observed in childhood, but no differences were identified for aphthosis and cervical adenopathy. Conversely, joint symptoms, myalgia, headache, fatigue, ocular signs, and rashes were more common in adults. The simultaneous occurrence of two or three cardinal PFAPA signs did not show any statistical difference between the groups, while the occurrence of only one cardinal manifestation was more frequent in adults. Corticosteroids were effective in 98.82% of children and 88.2% of adults. Tonsillectomy was rarely performed, resulting effective in only two patients. Our data illustrate the clinical overlap between pediatric and adult cases of PFAPA syndrome. Adults are characterized by a wider repertoire of inflammatory signs, suggesting that onset in adulthood might leave the disease misdiagnosed. Clinicians, not only pediatricians, should take into account this clinical entity in every patient of whatever age suffering from recurrent fevers of unknown origin.

To evaluate the effectiveness and the systemic corticosteroid sparing effect of a single intravitreal dexamethasone (DEX) implant in patients with chronic noninfectious uveitic macular edema (UME).Data from 22 eyes treated with DEX implant for UME related to systemic or ocular-confined noninfectious diseases were retrospectively analyzed.The mean systemic prednisone (or equivalent) dosage significantly decreased at 3- and 6-month follow-up evaluations compared to baseline (P = 0.002 and P = 0.01, respectively). Compared to baseline, central macular thickness values significantly decreased at 1-, 3-, and 6-month evaluations after the implantation (P 0.0001). The mean best corrected visual acuity (BCVA) value gradually improved at 1-, 3-, and 6-month visits compared to baseline (P = 0.009, P = 0.0004, and P = 0.0001, respectively). At fluorescein angiography, active retinal vasculitis was identified in 11 (50%) eyes at baseline, 3 (13.6%) eyes at 1- and 3-month follow-up, and in 2 (9.1%) eyes at the last visit. Regarding side effects, 3/22 (13.6%) eyes presented a newly recognized intraocular hypertension at 1-month follow-up; however, intraocular pressure reverted to normal values within the 6-month follow-up in all cases.Treatment with intravitreal DEX implant in noninfectious uveitis allowed a significant corticosteroid sparing effect, a significant improvement in BCVA, and a prompt resolution of UME and vasculitis. No safety issues were observed.

Background Remission is the current aim of early RA treatment. In patients with early, aggressive RA, combination with adalimumab (ADA) plus methotrexate (MTX) was superior to either MTX or ADA alone in obtaining clinical remission. Moreover, it has been demonstrated that a short-term aggressive treatment with high-dose glucocorticoids (GC) plus conventional DMARDs lead to long-term (up to 5 years) benefits. Objectives To compare the proportion of patients who achieve remission at 12 months, between two groups of subjects treated with ADA + MTX + high dose GC (intensive) and ADA + MTX + placebo (standard), and to evaluate the proportion of those maintaining remission at 24 months, after discontinuation of GC at 6 and ADA at 12 months. Methods The main inclusion criteria were: active RA, disease duration ≤1 year, GC and MTX-naivity, at least one predictor of aggressive disease. All subjects received ADA for 12 months and MTX (20 mg/w) to the end of month 24. Subjects were randomized to receive prednisone (orally, 50 mg/d, progressively tapered to 6.25 mg and stopped at month 6) or placebo. Response was evaluated using DAS28, CDAI, SDAI and ACR response criteria. The difference in rate and 95% CI will be computed with a binomial regression model and identity link, while clustering on center. An intention-to-treat analysis was performed. Results 118 patients were assigned to standard and 115 patients to intensive group. Remission (DAS28 Conclusions Our results confirm that intensive treatment with biologics in early, aggressive RA might be considered to induce and maintain clinical remission. The addition of high-dose GC to a first line treatment with ADA and MTX did not prove to induce a further improvement in efficacy. Although these results should be tested with other biologic therapies, the high rate of drop out for AE in the intensive group should be carefully considered in the risk-benefit ratio. Disclosure of Interest None declared

The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1βand tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.

We thank Agca and colleagues1 for their valuable comments on our correspondence ‘Influence of changes in cholesterol levels and disease activity on the 10-years cardiovascular risk estimated with different algorithms in rheumatoid arthritis patients’.2 They highlighted the complexity of cardiovascular (CV) risk assessment in patients with rheumatoid arthritis (RA), with some aspects that need to be clarified. The purpose of our study was not to determine if possible changes in CV risk scores during the first 6 months of treatment with biologic agents reflect reality, for which we need, as suggested, much larger cohorts, but rather to evaluate how the changes in disease activity and lipid levels may differently impact on CV risk algorithms commonly used by physicians in their daily clinical practice. In our RA cohort we selected all patients who started a first-line biologic agent since January 2010 with all available data …

European League Against Rheumatism (EULAR) recommendations for cardiovascular (CV) risk management in patients with Rheumatoid Arthritis (RA) suggest to ‘measure cholesterol and other lipid fractions when disease activity is stable or in remission’.1 This point ensues from the assumption that inflammation and high disease activity can lower lipid levels and mislead the CV risk score, despite the risk of CV disease is reported to be increased in patients with active RA.2 As algorithms used in clinical practice include total cholesterol (Tot-Chol) and its fractions as variable of interest, we would like to raise the question whether lipid levels and disease activity changes during the first months of biological treatment may have an impact on the ordinary CV risk scores. We analysed RA patients included in the BIOlogic aPUlian REgistry (BIOPURE) (Ethics Review Board of Policlinico of Bari, comitatoetico@policlinico.ba.it, protocol number 5277), who started a first-line biological agent since …

Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients’ quality of life. IL-1β blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1β antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.

Objective.An observational study to evaluate the longterm clinical outcomes of adalimumab (ADA), etanercept (ETN), and infliximab (IFX) in patients with psoriatic arthritis (PsA), in real-world settings.Methods.From a prospective cohort we studied 420 biologic-naive patients with PsA who had peripheral arthritis and were beginning a treatment with ADA, ETN, or IFX. Drug survival was evaluated by Kaplan-Meier life analysis, and baseline predictors of drug discontinuation were assessed by Cox regression analysis. The frequency of concomitant glucocorticoids and the daily mean dosage were compared by chi-square test and ANOVA repeated measures across 4 years.Results.After 4 years the overall survival of the first anti-tumor necrosis factor-α (anti-TNF) was 51.0%, but significantly higher for ETN (58.9%) than ADA (43.9%) or IFX (44.0%; p = 0.003). Patients taking ETN also had the lowest HR of drug discontinuation (HR 0.57, 95% CI 0.34–0.93, p = 0.02). The strongest predictor of drug interruption was female sex (HR 2.02, 95% CI 1.28–3.20, p = 0.002). The disease duration was inversely correlated with drug discontinuation (HR 0.96, 95% CI 0.93–0.99, p = 0.02). The average daily dose of prednisone significantly decreased from baseline: 5.6 ± 2.5 to 4.7 ± 1.9 at 1 year (p = 0.01) to 4.0 ± 1.8 at 4 years (p = 0.001). Additionally, compared to baseline (49.6%), a significant reduction of patients taking glucocorticoids was detected at 2 years (36.5%, p < 0.05), 3 years (29.9%, p < 0.01), and 4 years (22.6%, p < 0.01).Conclusion.In real-world settings, TNF inhibitors showed a high rate of drug survival at 4 years. Further, the need for glucocorticoids for controlling active PsA was lowered with time.

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 are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.

Relapsing polychondritis is a rare multisystemic disease widely accepted as a complex autoimmune disorder affecting proteoglycan-rich structures and cartilaginous tissues, especially the auricular pinna, cartilage of the nose, tracheobronchial tree, eyes, and heart's connective components. The clinical spectrum may vary from intermittent inflammatory episodes leading to unesthetic structural deformities to life-threatening cardiopulmonary manifestations, such as airway collapse and valvular regurgitation. The frequent association with other rheumatologic and hematologic disorders has been extensively reported over time, contributing to define its complexity at a diagnostic and also therapeutic level. Diagnosis of relapsing polychondritis is mainly based on clinical clues, while laboratory data have only a supportive contribution. Conversely, radiology is showing a relevant role in estimating the rate of systemic involvement as well as disease activity. The present review is aimed at providing an update on scientific data reported during the last 3 years about relapsing polychondritis in terms of pathogenesis, clinical features, diagnosis, and new treatment options.

The purpose of the present review was to provide a comprehensive picture of the efficacy of the different tumor necrosis factor (TNF)-α inhibiting agents in the treatment of acute anterior uveitis (AAU), the most common extra-articular manifestation of ankylosing spondylitis (AS). AS related, AAU may lead to severe visual impairment, due to frequent flare recurrences, anterior, and posterior segment complications and traditional treatment side effects. Considerably higher levels of tumor necrosis factor (TNF) have been assessed in the aqueous humor and inflamed joints of patients with AS. Anti-TNF drugs have shown efficacy in preventing relapses of rheumatological manifestations of spondyloarthropathies. Several studies have underlined the sustained efficacy of the monoclonal anti-TNF antibodies also in reducing the recurrence of anterior chamber flares in patients with AS-related AAU. On the other hand, retrospective studies and observational reports have indicated lower effectiveness and some paradoxical occurrence of uveitis following treatment with the soluble receptor agent etanercept. Growing evidence suggests that a prophylactic strategy could be advocated in subjects with frequent and recalcitrant attacks of AS-AAU. In this regard, the administration of monoclonal anti-TNF antibodies such as adalimumab (ADA) has been shown to significantly reduce the rate of AAU recurrences. Indeed, during ADA treatment about 90 % of patients have shown to remain completely free of attacks for the entire follow-up period, in most studies. Further studies are needed to confirm the long-term efficacy of TNF inhibitors in AS related AAU and also their role in preventing ocular complications and visual impairment.

The main outcomes of the therapies for rheumatoid arthritis (RA) must be preventing, or at least lessening, the development of structural damage. Biological disease-modifying anti-rheumatic drugs (bDMARDs), targeting tumour necrosis factor-α (TNF-α) or other key steps (IL-1, IL-6, T cells, B cells) in the pathogenesis of RA, have given clues to be effective and safe as treatments for RA, being capable of improving disease activity, ameliorating functional ability and halting joint damage. A large body of evidence, stemming from randomized clinical trials, observational studies, and registries, has shown that the beneficial effects of the bDMARDs become optimal when combined with synthetic (s)-DMARDs, mainly methotrexate (MTX). Despite combination therapy is advocated by the international guidelines for the management of RA, data from the daily standard of care indicate that almost one third of RA patients are treated with bDMARDs as monotherapy. Many reasons may be taken into account to explain this gap from official recommendations, among which the fact that in real-life settings, the assessment of clinical outcomes is exclusively based on clinical indices, disregarding the evolution of bone damage. Furthermore, some bDMARDs have been launched in the market with the official approval to be used as monotherapy. But even for the latter, there is no conclusive proof that monotherapy regimen is comparable to co-therapy with MTX in preventing articular damage. In conclusion, the most recent published data show that combination therapy with bDMARDs and MTX represents the best therapeutic option for the treatment of RA since it can stop or at least slow the progression of disabling structural damage.

Inflammation mediated by cells of the immune system and necrosis are the most striking features observed at the histologic level in patients with vasculitides, clinical entities classified according to pathologic findings involving different organs, to etiology, or to size of vessels involved. Small vessel vasculitides (SVV) are a peculiar group of systemic disorders electively involving small intraparenchymal arteries, arterioles, capillaries, or venules and leading to different levels of vascular obstruction, tissue ischemia and risk of infarction; they can be divided into anti-neutrophil cytoplasmic antibody-associated vasculitides and immune complex vasculitides. Despite the significant advances in understanding the whole disease process and pathophysiology of SVV, strong efforts are still needed to draft, share and spread guidelines in the therapeutic management of these protean disorders. After an accurate evaluation of different open or double-blind trials and cohort studies in this review, we analyze the actual medical tools suggested for treating granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, anti-glomerular basement membrane disease and hypocomplementemic urticarial vasculitis.

Auto-antibodies against aminoacyl-tRNA-synthetases (anti-ARS Abs) represent the hallmark of the anti-synthetase syndrome that is defined as the clinical association of fever, Raynaud's phenomenon, myositis, interstitial lung disease (ILD), arthritis and mechanic's hands. Recently, differences in clinical features depending on specific anti-ARS Abs have been reported. We describe three cases of anti-EJ (anti-glycyl) antibody-positive patients presenting with ILD as a common feature, but with heterogeneous histopathological and radiographic patterns and with different responses to treatment. Relapsing-remittent fever, refractory muscle involvement and seronegative arthritis were also striking clinical manifestations.

We report on a patient with a long-standing history of recurrent oral aphthosis and pseudofolliculitis, diagnosed with Behçet's disease (BD), previously treated with high-dose prednisone, colchicine, cyclosporine, cyclophosphamide and methotrexate, all of which were partially effective. Treatment with the chimeric mouse-human anti-tumour necrosis factor (TNF)-α monoclonal antibody infliximab brought about the resolution of mucocutaneous lesions for a period of 6 years. After an oral and articular BD relapse, the anti-interleukin-6 agent tocilizumab was started in association with high-dose prednisone. Unexpectedly, the patient experienced a paradoxical mucocutaneous flare following tocilizumab administration, which worsened after the second infusion. Tocilizumab was then discontinued, and total recovery was achieved after the patient was started on the fully human anti-TNF-α monoclonal antibody golimumab in association with colchicine and methylprednisolone.

In the original version of this article the author name Gerardo Di Scala was originally presented incorrectly as 'Di Scala Gerardo'; this has been corrected in this article.

Behcet's disease (BD) is a multisystemic disorder of unknown etiology characterized by relapsing oral–genital ulcers, uveitis, and involvement of vascular, gastrointestinal, neurological, and musculoskeletal system. Although disease pathogenesis is still unclear, both innate and adaptive immunity have shown to play a pivotal role, and multiple proinflammatory cytokines seem to be involved in different pathogenic pathways that eventually lead to tissue damage. The aims of our study were to evaluate serum cytokines levels of IL-8, IL-18, IFN-α2a, IL-6, IFN-γ, CXCL10, CXCL11, CXCL9, and SAA levels in patients with BD, in comparison to healthy controls (HC), and to correlate their levels to disease activity. We included 78 serum samples obtained from 58 BD patients and analyzed a set of proinflammatory cytokines including IL-8, IL-18, IFN-α2a, IL-6, IFN-γ, CXCL10, CXCL11, and CXCL9 by multiplex bead analysis as well as SAA by enzyme-linked immunosorbent assay. Compared to HC, BD patients showed elevated cytokine levels of IL-8, IL-18, IFN-α2a, and IL-6, and low levels of CXCL11. BD patients with SAA serum levels >20 mg/L showed higher levels of proinflammatory markers than HC or group with SAA ≤20 mg/L. IL-18, IFN-α2a, and IL-6 were higher in BD group with SAA >20 mg/L than HC, while IL-8 and CXCL9 levels were higher than in patients with SAA ≤20 mg/L and HC. Active BD patients with SAA >20 mg/L exhibited elevated levels of inflammatory mediators, suggesting that may exist a relationship between SAA and proinflammatory cytokines in the intricate scenario of BD pathogenesis.

Epidermolysis bullosa (EB) is a rare disorder characterized by inherited skin adhesion defects with abnormal disruption of the epidermal–dermal junction in response to mechanical trauma. Our aim was to investigate a set of cytokine levels in serum samples from patients suffering from epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and healthy controls (HCs), exploring their potential correlations with antiskin autoantibody titers and disease activity. Forty patients afferent to the Dermatological Ward of Bari City Hospital and 9 HCs were enrolled and subdivided according to the dystrophic (DEB) and simplex forms (EBS). We found a significant increase in interleukin (IL)-1β plasmatic levels of DEB (P = 0.0224) and EBS (P = 0.0465) patients compared to HCs; IL-6 levels were significantly higher in DEB than in EBS patients (P = 0.0004) or HCs (P = 0.0474); IL-2 levels were significantly increased in DEB compared with EBS (P = 0.0428). Plasmatic tumor necrosis factor-β and interferon-γ were higher in DEB patients than in HCs (P = 0.0448 and 0.0229). Conversely, tumor necrosis factor-α was significantly decreased in DEB (P = 0.0034). IL-5 correlated with anti-BP180 (r = −0.5018, P = 0.0338), anti-BP230 (r = −0.6097, P = 0.0122), and anticollagen VII (r = −0.5166, P = 0.0405) autoantibodies; interferon-γ correlated with anti-BP180 (r = 0.9633, P

We read with interest the paper by Nwosu et al 1 recently published in Annals of the Rheumatic Diseases . They clearly provided evidence that blocking tropomyosin receptor kinase A (TrkA), the p140 high-affinity receptor of nerve growth factor (NGF), by a selective TrkA inhibitor AR786 relieves pain in two different rat models of osteoarthritis (OA). A reduction of synovitis was also shown by histopathology, suggesting that NGF inhibition exerted its effect at peripheral level on extraneural tissues. Authors concluded that inhibition of NGF activity might be an effective strategy as treatment of OA pain. Indeed, NGF may have pleiotropic effects, and we would like to speculate on the possible role played by NGF and its counter-receptor …

Giant cell tumor (GCT) of the synovial membrane, also known as pigmented villonodular synovitis, causes a progressive, relapsing and destructive arthropathy affecting one or more synovial joints. Systemic therapy can be combined to intra-articular treatments, including surgical synoviectomy, especially when monoarticular. Despite that, the synovial membrane commonly grows again with clinical relapse. Here, we report three case of patients diagnosed with GCT of the knee who had an early relapse of the disease even after surgical synoviectomy. All of them underwent intra-articular therapy with infliximab and subsequent synoviectomy to eradicate residual tissue. A complete remission of CGT was achieved without relapse occurring during the follow-up. These preliminary data need to be confirmed by further clinical trials; however, intra-articular therapy with infliximab might be deemed a potential option to treat CGT of a single joint.

Behçet’s disease (BD) is a multisystemic disorder of unknown etiology characterized by the “triple symptom complex” consisting of recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis. Recurrent mucocutaneous lesions are generally considered the hallmark of the disease, being the most common symptoms presenting at the onset of disease. Although the improvement of knowledge about the pathogenetic mechanism added important changes in the treatment management of BD clinical manifestations, thus avoiding the appearance of serious life-threatening complications which are disease related, the mucocutaneous lesions are still the most nagging clinical manifestations to be treated. In this work we reviewed the current state of knowledge regarding the therapeutic approaches for mucocutaneous lesions of BD mainly based on controlled studies to provide a rational framework for selecting the appropriate therapy for treating these troublesome features of the disease.

Growing data have provided encouraging results on the use of interleukin (IL)-1 inhibitors in Behcet’s disease (BD). This study was aimed at reporting the largest experience with anti-IL-1 agents in BD patients. We evaluated 30 BD patients receiving treatment with anti-IL-1 agents. The primary aims of the study were to evaluate the efficacy of anakinra (ANA) and canakinumab (CAN) in a cohort of BD. The secondary aims were to evaluate the overall safety profile of the treatments, explore the timing of response to therapy and any adjustment of dosage and frequency of drugs studied, and investigate predictive factors of response to therapy. The frequency of first line therapy was 90 % with ANA and 10 % with CAN. The overall number of subjects in complete remission after 12 months of therapy with anti-IL-1 drugs was 13: 6 maintained the initial therapy regimen, 1 maintained the same initial anti-IL-1 drug with further therapeutic adjustments, and the remaining 6 shifted from ANA to CAN. Among them, 3 used CAN for at least 12 months without therapeutic adjustments, 1 had therapeutic adjustments, and 3 had an overall history of a 12-month complete remission. Adverse events (AEs) were reported in 15 % patients who received ANA, represented in all cases by local cutaneous reactions, while no AE were observed in patients who received CAN; we did not observe any serious AEs (SAEs) during the follow-up period. Our data have confirmed that the use of anti-IL-1β drugs is efficacious and safe with an overall acceptable retention on treatment.

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.

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.

The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.

Autoimmunity and autoinflammation are generally considered as mutually exclusive mechanisms of diseases but may concur to specific syndromes. Idiopathic recurrent acute pericarditis (IRAP) is defined as the recurrence of pericardial symptoms at any point following the prior cessation of acute pericarditis, and the latency is generally 6 weeks. Manifestations of pericarditis such as pericardial friction rub, electrocardiographic changes, and pericardial effusion are less frequent in the subsequent episodes compared to the index attack, and in some cases the only clinical sign is represented by a suggestive chest pain. Several autoimmune diseases may manifest with pericarditis which is often related to viral infections, while postviral pericarditis may in turn display a nonspecific autoimmune background. Similarly, autoinflammatory syndromes such as familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome are characterized by self-limiting pericardial symptoms. Corticosteroids are generally effective, thus supporting the autoimmune nature of IRAP, but dramatic results are obtained with interleukin-1 blocking agents in corticosteroid-dependent cases, pointing to a pathogenic role for the inflammasome. Based on these observations, we submit that IRAP represents a paradigmatic example of the putative coexistence of autoimmunity and autoinflammation: the main aim of this review is to critically discuss the hypothesis as well as the current understanding of this enigmatic clinical condition.

European and Asian studies report conflicting data on the risk of hepatitis B virus (HBV) reactivation in rheumatologic patients with a previously resolved HBV (prHBV) infection undergoing long-term biologic therapies. In this patient category, the safety of different immunosuppressive biologic therapies, including rituximab, was assessed. A total of 1218 Caucasian rheumatologic patients, admitted consecutively as outpatients between 2001 and 2012 and taking biologic therapies, underwent evaluation of anti–HCV and HBV markers as well as liver amino transferases every 3 months. Starting from January 2009, HBV DNA monitoring was performed in patients with a prHBV infection who had started immunosuppressive biologic therapy both before and after 2009. Patients were considered to have elevated aminotransferase levels if values were >1× upper normal limit at least once during follow-up. We found 179 patients with a prHBV infection (14 treated with rituximab, 146 with anti–tumor necrosis factor-alpha, and 19 with other biologic therapies) and 959 patients without a prHBV infection or other liver disease (controls). The mean age in the former group was significantly higher than the controls. Patients with a prHBV infection never showed detectable HBV DNA serum levels or antibody to hepatitis B surface antigen/hepatitis B surface antigen seroreversion. However, when the prevalence of elevated amino transferases in patients with prHBV infection was compared to controls, it was significantly higher in the former group only for aminotransferase levels >1× upper normal limit but not when aminotransferase levels >2× upper normal limit were considered. Conclusion: Among patients with a prHBV infection and rheumatologic indications for long-term biologic therapies, HBV reactivation was not seen; this suggests that universal prophylaxis is not justified and is not cost-effective in this clinical setting. (Hepatology 2015;62:40-46)

Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates' role in the scenery of autoinflammatory disorders.

Serum amyloid-A (SAA) is an acute phase protein, synthesized by the liver and previously investigated as a marker of disease activity in many rheumatologic disorders. Its significance in Behcet’s disease (BD), a chronic inflammatory disorder at the crossroad between autoimmune and autoinflammatory syndromes, is still unraveled. Our aim was to assess the role of SAA levels as a potential marker of disease activity in patients with BD. According to our findings, the occurrence of oral aphthosis, neurological impairment, and ocular disease is significantly associated with SAA serum levels higher than 30, 50, and 150 mg/L, respectively. We also suggest that increased SAA levels might identify a thrombotic risk in BD with previous or concurrent vascular involvement.

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. © 2014 Clinical Rheumatology.

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combining autoimmune and autoinflammatory pathways has been hypothesized to explain its start and recurrence. In-depth analysis of BD pathogenetic mechanisms, involving dysfunction of multiple proinflammatory molecules, has opened new modalities of treatment: different agents targeting interleukin-1 have been studied in recent years to manage the most difficult and multi-resistant cases of BD. Growing experience with anakinra, canakinumab and gevokizumab is discussed in this review, highlighting the relative efficacy of each drug upon the protean BD clinical manifestations. Safety and tolerability of interleukin-1 antagonists in different doses have been confirmed by numerous observational studies on both large and small cohorts of patients with BD. In particular, the potential for Mycobacterium tuberculosis reactivation and tuberculosis development appears to be significantly lower with interleukin-1 blockers compared to tumor necrosis factor-α inhibitors, thus increasing the beneficial profile of this approach.

Autoinflammatory disorders (AIDs) are a novel class of diseases elicited by mutations in genes regulating the homeostasis of innate immune complexes, named inflammasomes, which lead to uncontrolled oversecretion of the proinflammatory cytokine interleukin-1β. Protean inflammatory symptoms are variably associated with periodic fever, depicting multiple specific conditions. Childhood is usually the lifetime in which most hereditary AIDs start, though still a relevant number of patients may experience a delayed disease onset and receive a definite diagnosis during adulthood. As a major referral laboratory for patients with recurrent fevers, we have tested samples from 787 patients in the period September 2007–March 2014, with a total of 1,328 AID-related genes evaluated and a gene/patient ratio of 1.69. In this report, we describe our experience in the clinical approach to AIDs, highlight the most striking differences between child and adult-onset AIDs, and shed an eye-opening insight into their diagnostic process.