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Abstract Background and Objective Clodronate is a nitrogen-free bisphosphonate that is widely and effectively used in the treatment of many osteo-metabolic disorders. The objective of our study was to evaluate the effectiveness of clodronate in reducing pain and bone marrow edema in knee osteoarthritis. Methods In total, 74 patients were included in the study. Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months. Visual analog scale (VAS) scores were recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). We also evaluated functional status and use of paracetamol (T0, T1, T2, T3, T4, and T5) and changes in Whole Organ Magnetic Resonance Imaging Score (WORMS; T0, T2, and T5). Results Both groups had a statistically significant reduction in VAS score until 3 months. Group 1 then experienced further VAS reductions, whereas VAS scores for group 2 progressively increased. Pain, stiffness, and physical function also showed the same trend, as did bone marrow edema extension, which was evaluated with WORMS. Conclusion Our study indicates that intramuscular administration of a therapeutic dose of clodronate followed by a maintenance dose is effective in the management of symptomatic knee osteoarthritis, improving functional outcomes and reducing pain and bone marrow edema. Prolonged treatment increases the long-term efficacy of clodronate compared with the shorter schedule.

Objectives: Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries. Methods: Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison. Results: Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042). Conclusions: UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients.

Fibromyalgia, also known as fibromyalgia syndrome (FM), is a rheumatic syndrome which is currently considered idiopathic and multifactorial. It causes an increase in muscle tension associated with stiffness, asthenia (loss of strength with fatigue), cognitive impairment, insomnia or sleep disorders and impaired sensitivity to stimuli. We performed a prospective evaluation of 149 patients suffering from fibromyalgia syndrome according to the 2010 ACR Criteria. Patients were clinically assessed at baseline and after 1-3-6 months, using the patient-reported outcomes thermometer - 5-item scale (5TPROs). In addition to their therapy, all patients received a supplementation with Spilanthes Achmella. This food supplement is characterized by synergy of bioactive compounds, such as Acmella oleracea extract, and has neurotrophic, anti-inflammatory and pain-relieving effects. All patients were randomized at baseline to receive Spilanthes Achmella, 2 tablets per day for one month and subsequent tapering to 1 tablet per day for 5 months. At six months, a statistically significant difference in the following parameters was shown: pain P

Background: There is little consensus on ultrasound (US) normative values of cross-sectional area of median nerve (MN-CSA) in carpal tunnel syndrome (CTS) because of its dependency on anthropometric parameters. We aim to propose a novel anthropometric-independent US parameter: MN-CSA/flexor radialis carpi CSA (FCR-CSA) ratio (“Nerve Tendon Ratio”, NTR), in the diagnosis of clinically and electrodiagnostic (EDS)-defined CTS. Methods: 74 wrists of 49 patients with clinically defined CTS underwent EDS (scored by the 1–5 Padua Scale of electrophysiological severity, PS) and US of carpal tunnel with measurement of MN-CSA (at the carpal tunnel inlet), FCR-CSA (over scaphoid tubercle) and its ratio (NTR, expressed as a percentage). US normality values and intra-operator agreement were assessed in 33 healthy volunteers. Results: In controls, the mean MN-CSA was 5.81 mm2, NTR 64.2%. In 74 clinical CTS, the mean MN-CSA was 12.1 mm2, NTR 117%. In severe CTS (PS > 3), the mean MN-CSA was 15.9 mm2, NTR 148%. In CTS, both MN-CSA and NTR correlated with sensitive conduction velocity (SCV) (p < 0.001), distal motor latency (DML) (p < 0.001) and PS (p < 0.001), with a slight superiority of NTR vs. MN-CSA when controlled for height, wrist circumference and weight. In CTS filtered for anthropometric extremes, only NTR maintained a correlation with SCV (p = 0.023), DML (p = 0.016) and PS (p = 0.009). Diagnostic cut-offs were obtained with a binomial regression analysis. In those patients with a clinical diagnosis of CTS, the cut-off of MN-CSA (AUROC: 0.983) was 8 mm2 (9 mm2 with highest positive predictive value, PPV), while for NTR (AUROC: 0.987), the cut-off was 83% (100% with highest PPV). In patients with EDS findings of severe CTS (PS > 3), the MN-CSA (AUROC: 0.876) cut-off was 12.3 mm2 (15.3 mm2 with highest PPV), while for NTR (AUROC: 0.858) it was 116.2% (146.0% with highest PPV). Conclusions: NTR can be simply and quickly calculated, and it can be used in anthropometric extremes.

Background: This study aims at describing the therapeutic outcome of patients carrying the R92Q variant in the TNFRSF1A gene treated with anakinra (ANA) or canakinumab (CAN) and identifying any factors predictive of complete response to IL-1 inhibition. Methods: Clinical data of patients treated with ANA or CAN for recurrent inflammatory attacks due to the presence of the R92Q variant were retrospectively collected and analysed. Results: Data about 20 treatment courses with IL-1 inhibitors (16 with ANA and 4 with CAN) from 19 patients were collected. Mean age at disease onset was 20.2 ± 14.8 years. In 5 cases (26%) the R92Q variant was found in a family member affected by recurrent fever. The therapeutic response was complete in 13(68%) and partial in 2 patients (11%); treatment failure was observed in 4 cases (21%). Median AIDAI decreased from 10 (interquartile range [IQR] = 28) to 0 (IQR = 1) at the 12-month follow-up visit ( p

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response.Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers.Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001–0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301–0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed.Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.

Aims: Medical and non-medical switching strategies have been adopted in Europe in the last few years. We aimed to investigate persistence on treatment with a SB5 Adalimumab (SB5) biosimilar after switching from Adalimumab (ADA) originator among patients with inflammatory rheumatic musculoskeletal diseases (iRMD), identifying possible predictors of drug interruption and describing adverse events. Method: iRMD patients previously switched to SB5 after at least 6 months of ADA were enrolled. Data on concomitant medications, disease flares, and persistence on SB5 up to the last available follow up were collected retrospectively. Kaplan–Meier and Cox regression models were used. Result: A total of 172 patients (106 females, ADA duration 5.8 ± 3.8 years) were enrolled, including 34 rheumatoid arthritis, 59 psoriatic arthritis, and 61 axial spondyloarthritis patients. In a 10 ± 3 months follow up, 65 (37.8%) patients presented with adverse events, with 46 (26.7%) showing a clinically defined disease flare (no disease activity and patient reported outcomes assessment were available); 24 patients interrupted SB5 permanently (among them, 11 back-switched to ADA and 8 were prescribed a different biological therapy). Probability of persistence on SB5 was 94.7% at 6 months and 85.1% at 12 months. Baseline corticosteroid [hazard ratio (HR) 3.209, 95% confidence interval (CI) 1.193–8.635, p = 0.021] and therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) (HR 2.876, 95% CI 1.229–6.727, p = 0.015), as well as the baseline corticosteroid dose (HR 1.200, 95%CI 1.026–1.403, p = 0.022) were predictors of drug interruption. Conclusion: Our data on persistence of treatment and adverse events are in line with previous reports. Further large cohort studies may confirm baseline corticosteroid and NSAIDs use as predictors of SB5 interruption, helping to identify patients at higher risk of failure after switching.

Background: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients. Methods: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate ( N = 41) given once daily for 16 consecutive days or placebo control ( N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed. Results: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls. Trial registration: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28

Background: Power Doppler ultrasound (PDUS) with spectral wave analysis (SWA) has been compared with magnetic resonance imaging (MRI) in documenting active sacroiliitis in early spondyloarthritis (SpA) but, to date, PDUS/SWA has not been yet applied to the study of sacroiliac joints (SIJs) in children. Methods: A group of 20 children (13 F/7 M, mean age 14.2 y) with suspected juvenile SpA (jSpA) underwent PDUS/SWA and, subsequently, MRI of the SIJs. SIJs PDUS scoring and resistance index (RI) of the SIJs flows were recorded. The accuracy of PDUS/SWA for the diagnosis of active sacroiliitis was evaluated, with MRI as the gold standard. Results: PDUS signals were detected in 19 patients and 30 SIJs. Bone marrow edema (BME) lesions on MRI were detected in 12 patients (diagnosed as jSpA) and 22 SIJs. PDUS scoring on SIJs were higher in patients with a final diagnosis of jSpA (p = 0.003). On SWA, the mean RIs in patients with or without final diagnosis of active sacroiliitis were, respectively, 0.604 and 0.767 (p = 0.005) at joint level. A RI < 0.55 and PDUS > 1 showed the higher specificity for sacroiliitis (AUROC curve 0.854 for PDUS and 0.920 for RI). SIJs PDUS/SWA showed an overall concordance of 82.35%, with substantial agreement (k = 0.627) with MRI on the diagnosis of sacroiliitis. Conclusions: In children with sacroiliitis, PDUS demonstrates a rich vascularization into SIJs and low RIs (

Aims: Switching from originator to biosimilar is part of current practice in inflammatory rheumatic musculoskeletal diseases (iRMDs) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA), with evidences derived from both etanercept (ETN) to SB4-switching randomized controlled trials and real-life registries. We investigated the safety and treatment persistence of ETN/SB4 in a multi-iRMD cohort derived from two rheumatology departments in our region. Methods: Adult patients with iRMDs, treated with ETN for at least 6 months and switched to SB4 in stable clinical condition, were eligible for this retrospective evaluation. Retrospective data on adverse events, loss of efficacy and persistence on treatment were collected until latest available follow-up. Results: A total of 220 patients (85 RA, 81 PsA, 33 axSpA, 14 juvenile idiopathic arthritis and seven other conditions; 142 females, mean age 58 ± 7 years, disease duration 12 ± 4 years, ETN duration 7 ± 4 years) were enrolled, with median follow-up of 12.1 (9.7–15.8) months. A total of 50 patients (22.7%) presented with at least one adverse event, with 36 (16.4%) disease flares and 30 (13.6%: 11 for safety and 19 loss of efficacy) SB4 withdrawals. Cumulative SB4 treatment persistence was 99.1%, 88.6% and 64.6% at 6, 12 and 18 months respectively. Back-switch to ETN was performed in 17/30 cases, the remaining cases were managed with change of biologic disease modifying or conventional synthetic anti-rheumatic drug. Age was the only significant predictor of SB4 interruption at 6 months. Conclusion: Our real-life data confirm the safety profile of switching from ETN to SB4, with slightly higher treatment persistence rates compared with other real-life registries.

Background: The Coronavirus disease (COVID-19) pandemic is causing millions of infections and hundreds of thousands of deaths worldwide. Cumulative clinical and laboratory evidence suggest that a subset of patients with severe COVID-19 may develop a cytokine storm syndrome during the course of the disease, with severe respiratory impairment requiring ventilatory support. One field of research nowadays is to identify and treat viral-induced hyperinflammation with drugs used in other clinical conditions characterized by an hyperinflammation status. These drugs might help to reduce COVID19 mortality.Methods: Ruxolitinib, a JAK1 and JAK2 inhibitor, has been successfully used to treat severe immune-mediated diseases, such as graft vs. host disease and Hemophagocytic lymphohistiocytosis. We used ruxolitinib in 18 patients with clinically progressive COVID-19 related acute respiratory distress syndrome, with a primary endpoint to rapidly reduce the degree of respiratory impairment and as a secondary endpoint to rapidly restore the PaO2/FiO2 ratio, as an evaluation of clinical status, and monitoring of drug related Adverse Events. Parameters of inflammation responses and organ functions were assessed and monitored. The treatment plan was ruxolitinib 20 mg bid for the first 48 h and subsequent two-step de-escalation at 10 mg bid and 5 mg bid for a maximum of 14 days of treatment.Results: Our data collection shows a rapid clinical response with no evolution from non-invasive ventilation to mechanical ventilation in 16/18 patients and no response in two patients (overall response rate—ORR 89%). Already after 48 h of ruxolitinib treatment 16/18 patients showed evident clinical improvement, and after 7 days of treatment 11/18 patients showed fully recovered respiratory function (pO2 > 98% in spontaneous breathing), 4/18 patients had minimal oxygen requirement (2–4 L/m), 1/18 patient showed stable disease, and 2/18 patient showed progressive disease. After 14 days, 16/18 patients showed complete recovery of respiratory function (ORR 89%). Compliance to ruxolitinib planned treatment was 100% and no serious adverse event was recorded. In our case series of 18 critically ill patients with COVID-19 and ARDS, administration of ruxolitinib resulted in a clinical improvement that concurred to modify the standard course of disease. Ruxolitinib can be a therapeutic option for patients with respiratory insufficiency in COVID-19 related ARDS. RESPIRE Study (Ruxolitinib for the treatment of acute rESPIratory distREss syndrome, ClinicalTrials.gov Identifier: NCT04361903).

Background: Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment.Patients and Methods: One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences (p < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK.Results: No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months (p = 0.19, p = 0.14, and p = 0.81, respectively) or 12 months (p = 0.37, p = 0.23, and p = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment (p = 0.06, p = 0.19, and p = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset (p = 0.01), while no significance was identified at the 6 and 12 month assessments (p = 0.23 and p = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs (p < 0.017).Conclusions: Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.

Objective. To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods. Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results. 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p=0.42), between low- and high-penetrance mutations (p=0.62), and according to different dosages (p=0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions. Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.

Objectives. To examine demographic and clinical characteristics and long-term visual outcome in a cohort of Italian patients affected by Behçet’s uveitis (BU). Materials and Methods. Retrospective chart review of 47 patients with BU attending our unit between January 2018 and December 2019. Ophthalmologic manifestations, best-corrected visual acuity (BCVA), fluoroangiography and optical coherence tomography findings, and ocular complications were recorded. Predictive factors of a poor visual outcome and long-term complications were also investigated. Results. Forty-seven patients (23 males and 24 females) for a total of 84 eyes were enrolled. Uveitis was bilateral in 37 (78.7%) patients with panuveitis being the most frequent anatomical pattern (40 out of 84 eyes), whereas 27 eyes presented a posterior uveitis. Isolated anterior uveitis was detected in 16 eyes. A significant improvement of median BCVA between baseline and last follow-up values was detected (p=0.042). A higher risk of poor visual prognosis was observed in patients with uveitis duration greater than 15 years (p=0.019). A significant resolution of retinal vasculitis was detected between baseline and last follow-up evaluation (p

Objectives. The primary aim of our study was to evaluate long-term efficacy of secukinumab (SCK) in patients with axial spondyloarthritis (axSpA); secondary aims were to evaluate drug retention rate and to identify differences in the clinical and laboratory assessment according to axSpA clinical features, dosage administered, and biologic treatment lines. Patients and Methods. We collected clinical, demographical, and treatment data from 39 patients affected by axSpA consecutively treated with SCK. Laboratory assessment was based on inflammation parameters; clinical assessment was performed with the Ankylosing Spondylitis Disease Activity Score- (ASDAS-) CRP and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Data were recorded at baseline and every 3 months for the first year and then every 6 months in the second year. Results. Twelve males and 27 females were enrolled; both BASDAI and ASDAS-CRP showed a statistically significant reduction during the observation period (p

Introduction. Giant cell arteritis (GCA) is a large vessel (LV) vasculitis, mainly affecting elder patients. Monitoring GCA activity during tocilizumab (TCZ) treatment is an unmet need, since low serum levels of C-reactive protein (CRP) during treatment may underestimate disease activity. To date, few data are available on the role of different imaging techniques in monitoring GCA activity and response to treatment. We report herein a cohort of GCA patients treated with TCZ and followed up with multimodal imaging. Patients and Methods. We collected clinical, laboratory, and imaging data of 11 GCA patients treated with TCZ 162 mg subcutaneously every week. Disease activity was assessed at baseline and within 12 months from the start of treatment using different imaging techniques such as color Doppler ultrasonography (CDUS), magnetic resonance imaging/angiography (MRI/MRA), computed tomography angiography (CTA), and/or positron emission tomography (PET). Results. Four patients were affected by cranial and 7 by LV-GCA. All patients were treated with oral glucocorticoids (GCs) (mean dose 55.68 mg±8.19 of prednisone or equivalent) in combination with TCZ. Treatment was preceded in 5 cases by 3 intravenous boluses of 1000 mg methylprednisolone. A significant decrease of the mean dose of oral GCs was observed between baseline and the last follow-up visit (4.65±3.69 mg) (p=0.003). TCZ treatment significantly decreased erythrocyte sedimentation rate (p

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients’ data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p

Background. Interleukin-1 inhibition has revealed to be a successful treatment approach for patients with adult-onset Still’s disease (AOSD). However, real-life experience is focused on the use of anakinra, while data about canakinumab (CAN) are mainly based on case reports and small case series. Patients and Methods. Patients classified with AOSD according to Yamaguchi criteria and treated with CAN were consecutively enrolled. Their clinical and therapeutic data were retrospectively collected and statistically analysed to assess the role of CAN as a therapeutic opportunity in AOSD patients in terms of clinical and laboratory disease control along with corticosteroid-sparing effect. Results. Nine AOSD patients (8 females and 1 male) treated with CAN for 15.00±12.3 months were enrolled. Resolution of clinical manifestations was reported in 8/9 cases at the 3-month assessment; a significant decrease in the number of tender joints (p=0.009), swollen joints (p=0.027), and disease activity score on 28 joints-C-reactive protein (DAS28-CRP) (p=0.044) was observed during the study period. The systemic score of disease activity significantly decreased at the 3-month and 6-month assessments and at the last visit compared to the start of treatment (p=0.028, p=0.028, and p=0.018, respectively). The daily corticosteroid dosage was significantly reduced at the 3-month and at the last follow-up visits (p=0.017 and p=0.018, respectively). None of the patients experienced adverse events or severe adverse events during the follow-up. Conclusions. CAN has shown prompt and remarkable effectiveness in controlling AOSD activity in a real-life contest, with a significant glucocorticoid-sparing effect and an excellent safety profile.

Background: Deregulated neutrophil extracellular traps (NETs) formation is implicated in various diseases, including ANCA-associated vasculitis and pulmonary fibrosis (PF). Lung involvement is frequent in AAV, and interstitial lung diseases (ILDs) are strongly related to MPO-ANCA positivity and mainly reported in microscopic polyangiitis. The association between AAV and ILD is a strong indicator of poor prognosis and limited survival. Neutrophils, ANCA and NET interplay in PF development in AAV. This study aimed to review the literature concerning the implications of NET in lung fibrogenesis specifically focused on AAV associated with ILD, and the potential of NET as a theranostic marker. Methods: Through scoping review methodology, we used a descriptive thematic analysis to understand the pathogenic role of NETs in patients with AAV and pulmonary fibrosis and their further role as a theranostic marker of this disease. Results: The implications of NET in the pathogenesis of AAV and ILD, as well as an association between these two diseases, have been identified, but the underlying pathophysiological mechanisms are still unknown. The pharmacological or genetic inhibition of NET release reduces disease severity in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. In this regard, despite the lack of clinical data, we may hypothesise that an optimal management of AAV-ILD patients would require not only B-cells targeted therapy, but also NETs inhibition. Conclusion: Preliminary findings seem to display a lack of efficacy of traditional immunosuppressants, such as Rituximab, in this subset of patients, while to date no patients suffering from a definite ILD have been enrolled in clinical trials. Further insights would be provided by their employment, as a combination treatment, in common clinical practice. Although we can imagine that the inhibition of NETs in patients with AAV-ILD could reduce severity and mortality, we still lack the scientific basis that could improve our understanding of the disease from a molecular point of view.

Background: ANCA-associated vasculitis (AAV) are small vessel vasculitis distinguished between microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). The former may have interstitial lung disease (ILD) associated with high morbidity and mortality. Here, Krebs von den Lungen-6 (KL-6), a marker of fibrotic ILD, was assessed for distinguishing AAV patients with ILD from those without ILD, and whether its changes over time are correlated with disease activity. Materials and Methods: Thirteen AAV patients (eight females, mean age 61 ± 14.8 years) were enrolled: six MPA and six GPA. Serum samples were assayed for KL-6 concentrations (Fujirebio Europe, Belgium). To investigate potential binary classifiers for diagnosis of AAV-ILD, we constructed a regression decision tree model. Results: Higher serum KL-6 were in AAV-ILD compared with those without ILD (972.8 ± 398.5 vs 305.4 ± 93.9, p = 0.0040). Area under the receiver operating characteristics curve showed 100% of the diagnostic performance of KL-6 for identifying the ILD involvement (accuracy 91.7%) and the best cutoff value of 368 U/mL (sensitivity 100% and specificity 87.5%). The decision tree model showed a 33% improvement in class purity using a cut-off value of 513 U/mL to distinguish AAV patients with and without ILD. Stratifying AAV patients as MPA and GPA with and without ILD considering T0 and T1 KL-6, the model obtained an improvement of 40% for classifying GPA non-ILD with a T0 serum KL-6 cut-off value of 513 U/mL and a T1 KL-6 cut-off of 301 U/mL. A direct correlation was found between serum T0 KL-6 and T0 BVAS (r = 0.578, p = 0.044). Conclusion: Our multicenter study demonstrated KL-6 as a reliable, non-invasive, and easy-to-perform marker of ILD in AAV patients and its helpfulness for disease activity assessment. Changes in serum concentrations of KL-6 over time could be useful for monitoring AAV patients. Further study of KL-6 as a marker of response to therapy during long-term follow-up would also be worthwhile.

Background: Recent expiry of patents for tumor necrosis factor (TNF)-α inhibitors has led to the employment of biosimilars in clinical practice. The aim of the study was to identify any change in the control of ocular inflammatory manifestations among patients with non-infectious uveitis switching from an originator to a corresponding anti-TNF-α biosimilar.Methods: Thirty-seven consecutive patients (62 eyes involved) with non-infectious uveitis undergoing the switch from anti-TNF-α originators to biosimilars were retrospectively enrolled; the frequency of ocular flares before and after the switch as well as best corrected visual acuity (BCVA), central macular thickness (CMT), daily systemic corticosteroid intake, and frequency of uveitic macular edema (UME) at the switch and at the following assessments were statistically analysed.Results: The number of ocular flares during the 12 months preceding the switch was 16, corresponding to 3.6 flares/100 patients/12 months; the number of flares after the switch was 14, corresponding to 2.0 flares/100 patients/12 months. No statistically significant differences were identified in the frequency of flares (p = 0.84) and in the number of patients experiencing ocular flares (p = 0.39) between the twelve months preceding the switch and the period thereafter. No statistically significant changes were observed in the BCVA (p = 0.27), CMT (p = 0.50), frequency of UME (p = 0.57) and daily corticosteroid intake (p = 0.42) between the time of the switch and the last follow-up visit.Conclusions: The switch to biosimilars represents a feasible treatment choice associated with the maintenance of clinical efficacy in patients with non-infectious uveitis previously treated with the corresponding originator anti-TNF-α biologic agents.

BackgroundThe inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and findingsThis study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.ConclusionsIn this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.Trial registrationThe trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

ObjectiveTo identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO).MethodsWe enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data.ResultsAccording to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92; p

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.

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: 526 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 were 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

Objective. The study aim was to determine treatment persistence rates and to identify causes of discontinuation in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients in clinical practice. Methods. Patients treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) were retrospectively included. Treatment persistence rates were analyzed by means of a stepwise logistic regression. Differences between therapy duration were assessed by means of an analysis of variance model (ANOVA), while a chi-square test was used to evaluate relationships between therapies and causes of treatment discontinuation and the administration of concomitant disease-modifying antirheumatic drugs (DMARDs) among therapies and types of disease considering completed courses of therapy versus courses that were discontinued. Results. 268 patients received a total of 353 anti-TNF treatment courses (97 ADA, 180 ETA, and 76 INF). Comparison among therapies showed significant difference regarding the treatment persistence rates due to the contrast between ETA and INF (P=0.0062). We observed that 84.7% of patients were still responding after 6 months of follow-up. Comparison among diseases showed that there were significant differences between PsA and AS (P=0.0073) and PsA and PsA with predominant axial involvement (P=0.0467) in terms of duration of the therapy, while there were no significant differences with regard to the persistence rate. Conclusions. In this cohort, anti-TNF-α therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-α agent can be an effective option when, during the treatment of AS or PsA, therapy is suspended because of inefficacy or an adverse event. Combination therapy with DMARDs was associated with a better persistence rate.

Purpose. Ultrasonography (US) has been demonstrated to be an important tool in the diagnosis of calcium pyrophosphate (CPP) crystal deposition disease. The aim of our study was to individuate and describe possible pitfalls in US detection of such deposits in menisci. Patients and Methods. We enrolled all patients waiting to undergo knee replacement surgery due to osteoarthritis, for one-month period. Each patient underwent US examination of the knee, focusing on the menisci. After surgery, the menisci were examined by US, macroscopically and microscopically, using the microscopic analysis as the gold standard for CPP deposition. Results. 11 menisci of 6 patients have been studied. Ex vivo examination of menisci performed better in CPP identification than in vivo examination. The possible reasons of misinterpretation or misdiagnosis of the in vivo exam were identified and are extensively described in the paper. Also a new sign of CPP crystal deposits was found. Conclusions. This study permitted to highlight some difficulties in CPP crystal detection by US in menisci. Further studies are needed to define completely US CPP crystal aspect and to improve the sensibility and specificity of US in CPP deposition diagnosis.

Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.