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Cerebrovascular events (CE) are one of the most common and severe events in antiphospholipid syndrome (APS), a condition characterized by thrombosis and circulating anti-phospholipid antibodies (aPL). Seronegative APS (SN-APS) refers to a group of patients with clinical features of APS but persistently negative tests for “criteria aPL”: anti-cardiolipin antibodies (aCL) and anti-β2glycoprotein I antibodies detected by enzyme-linked immunosorbent assay (ELISA), and the lupus anticoagulant detected by clotting assays. We report a series of five cases of SN-APS in young or middle-aged patients who tested positive for “non-criteria” aPL. We retrospectively collected cases of SN-APS patients who experienced CE without an identified cause despite an extensive diagnostic work-up and tested negative for criteria aPL. All the patient sera were tested for aCL by immunostaining on thin-layer chromatography (TLC) and anti-vimentin/cardiolipin (aCL/Vim) by ELISA. We identified five cases of female patients aged 21 to 58 years, evaluated at the Rheumatology Unit and/or Stroke Unit/Emergency Department of the Sapienza University Hospital of Rome, “Policlinico Umberto I”. All patients presented a clinical history suggestive of APS. All the patients tested positive for aCL by TLC-immunostaining, and one patient was positive for aCL/Vim. In young or middle-aged patients with cryptogenic CE and a clinical history suggestive of APS, the use of new diagnostic tools for identifying aPL, if validated in future studies, could represent an important step in the prompt diagnosis of APS.

Objective. Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis. Methods. This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate. Results. This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3). Conclusions. Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Objective. To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. Methods. We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. Results. The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p

Following the restrictions on the reimbursability of Janus kinase inhibitors introduced by the Italian Medicines Agency, the Italian Society of Rheumatology has drafted this document to shed light on the clinical conditions and reimbursability criteria set out in the prescription forms.

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The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of Rheumatoid Arthritis (RA) by regulating multiple immune functions and cytokine production. The JAK inhibitor tofacitinib is effective in RA patients not responding to methotrexate or TNF-inhibitors. Since hyperactive autophagy has been associated with impaired apoptosis of RA fibroblast-like synoviocytes (FLS), we aimed to investigate the role of tofacitinib in modulating autophagy and apoptosis in these cells. FLS isolated from RA biopsies were cultured with tofacitinib in presence of autophagy inducer rapamycin and in serum deprivation condition. Levels of autophagy, apoptosis, and citrullinated proteins were analyzed by western blot, flow cytometry, immunocytofluorescence, and Real-Time PCR. Rapamycin induced an increase in RA-FLS autophagy while the levels of autophagy marker LC3-II were reduced after in vitro treatment with tofacitinib. The analysis of autophagic flux by specific fluorescence dye confirmed the reduction of autophagy in RA FLS. The treatment with tofacitinib did not influence apoptosis of RA FLS. Modulation of the autophagic process by tofacitinib did not significantly change citrullination. The results of this study demonstrate that tofacitinib is able to modulate autophagy of FLS contributing to its effectiveness in RA patients.

Category: Bunion Introduction/Purpose: The hallux valgus (HV) deformity results in progressive subluxation of the sesamoids from their position (station) under the plantar surface of the first metatarsal head. This subluxation may result in erosion of the crista that separates the sesamoid grooves due to contact with the tibial sesamoid during weightbearing. While previous work using weightbearing CT (WBCT) scans has suggested that tibial sesamoid position is associated with degenerative change of the sesamoid metatarsal joint (Katsui FAI), no studies have quantified the relationship between sesamoid metatarsal degenerative changes and sesamoid subluxation. The purpose of the current investigation is to examine the relationship of the volume of the crista to first metatarsal pronation and sesamoid station, using three-dimensional models of patients' deformities created from WBCT scans. Methods: Thirty-nine HV patients and nine normal subjects underwent weightbearing or simulated weightbearing CT (WBCT) imaging. Crista volume was determined using a line drawn to connect the nadir of each sulcus on either side of the intersesamoidal crista for the length of the crista (Figure 1). The Mann-Whitney U test was used to compare mean crista volume between HV and normal patients. WBCT scans were used to establish sesamoid position using a four-stage scale (Kim FAI 2015) and quantify first metatarsal pronation using 3D reconstructions as previously described (Campbell FAI 2018). Single-factor analysis of variance (ANOVA) tests were used to compared the crista volume and pronation angle between the four sesamoid stations. A linear regression was performed to determine whether crista volume was associated with the pronation angle. Spearman's rank coefficient (r) was used to test the relationship of the sesamoid station against the crista volume and pronation angle. Results: The mean crista volume in HV patients was 80.10 mm 3 +- 35 mm 3 and in normal subjects was 150.64 mm 3 +- 24 mm 3 , which differed significantly between the two groups (P

Category: Bunion Introduction/Purpose: Hallux valgus (HV) is a triplanar deformity of the first metatarsal in which the first metatarsal adducts, dorsiflexes, and pronates with an average increase in pronation between 2° and 8° compared with normal patients (Kimura JBJS, Campbell FAI). Despite these radiographic changes of the first metatarsal in patients with HV, no correlation between postoperative two-dimensional radiographic parameters and patient-reported outcomes has been reported (Thordarson FAI). The purpose of this study was to determine if a postoperative decrease in first metatarsal pronation (1MTPronation) was associated with changes in patient-reported outcomes as measured by the PROMIS physical function, pain interference, and pain intensity domains or recurrence rates in patients with HV who undergo a first tarsometatarsal fusion (modified Lapidus procedure). Methods: This study included thirty-nine consecutive HV patients who underwent a modified Lapidus procedure, had preoperative and >=2-year postoperative PROMIS scores, and had 1MTPronation measured using the previously described triplanar angle of pronation (FAI, in press) on preoperative and at least 5-month postoperative weightbearing CT scans. Multivariable regression analyses were used to investigate differences in the change in PROMIS domains preoperatively and 2-years postoperatively between patients with 'no change/increased 1MTPronation' and 'decreased 1MTPronation.' No differences in preoperative radiographic parameters or patient characteristics found between two groups. A secondary analysis using multivariable regression modeling was performed to determine if patients with a decrease in 1MTPronation between 2°-8° ('moderate pronation change') had greater improvements in PROMIS scores compared with 'minimal pronation change' (8°) groups. A log-binomal regression analysis was performed to identify if a decrease in 1MTPronation was associated with recurrence of the HV deformity (postoperative HVA>=20° Results: The decreased 1MTPronation group (n=26) had a statistically significant greater improvement in the PROMIS physical function scale by 7.2 points (95% confidence interval (CI) 2.1-12.3, P=0.007) compared to the no change/increased 1MTPronation group (n=13). There were no statistically significant differences in PROMIS pain interference (P=0.380) or pain intensity (P=0.443) scores between the two groups. The secondary analysis found that patients in the moderate pronation change group (n=15) had significantly better improvements in the PROMIS physical function and pain intensity domains than the minimal pronation change group (n=14) (Table 1). The moderate pronation change group also had greater improvements in the PROMIS pain interference and pain intensity domains than the substantial pronation (n=10) change group (Table 1). Recurrence rates were significantly lower in the decreased 1MTPronation pronation group when compared to the no change/increased 1MTPronation group (11.5% and 46.2%, respectively; risk ratio 0.25, 95% CI 0.07-0.84, P=0.025). Conclusion: In patients undergoing a modified Lapidus procedure for correction of their HV deformity, a postoperative decrease in pronation of the first metatarsal, especially between 2° and 8°, was associated with improvement in PROMIS scores at two- years postoperatively and a lower recurrence rate. These results suggest that the rotational component of the hallux valgus deformity may play an important role in outcomes following surgery, and consequently, surgeons should consider addressing but not overcorrecting the first metatarsal pronation deformity when performing a surgical procedure for the treatment of hallux valgus.

Abstract Background Diabetic macular edema (DME) is an important cause of vision loss and despite the anatomical and functional improvement achieved with treatment, there are reports of persistent DME regardless of continuous anti-VEGF therapy. The purpose of this study is to examine the effect of patients with DME previously treated with other anti-VEGF agents who are transitioned to intravitreal aflibercept (IAI) on a fixed dosing regimen. Methods This prospective study included 20 patients presenting with DME with a history of previous anti-VEGF treatment with ranibizumab or bevacizumab. Patients received a 2 mg (0.05 mL) IAI every 4 weeks until no evidence of fluid by optical coherence tomography (OCT) followed by a fixed dosing schedule of 2 mg IAI once every 8 weeks through 24 months. There was a pre-planned interim analysis of the mean absolute change from baseline central foveal thickness at month 6 as measured by OCT. Secondary outcomes included mean change from baseline in ETDRS visual acuity and anatomic parameters. Optical Coherence tomography angiography (OCTA) capillary perfusion density (CPD) after transitioning to IAI therapy were also reported. Results Average central subfield thickness on OCT at baseline was 419.7 ± 92.0 and improved to 303.8 ± 73.1 at 6-months (p

Abstract Background Optical coherence tomography angiography (OCTA) enables detailed, non-invasive assessment of ocular vasculature. This study uses OCTA imaging to evaluate choriocapillaris and retinal capillary perfusion density (CPD) changes in diabetic retinopathy following anti-vascular endothelial growth factor (VEGF) treatment. Methods Records of 38 eyes at a single institution were reviewed, grouped as non-diabetic controls (19 eyes), diabetes mellitus patients with diabetic retinopathy (DR, 19 eyes) and macular edema (DME). DR eyes were imaged at baseline, 6-months and 12-months after anti-VEGF treatment. Quantitative analyses assessed CPD of the choriocapillaris and retinal plexus. Results DR eyes showed decreased choriocapillaris whole-image CPD (62.6 ± 6.1 vs. 68.4 ± 5.1, p

The purpose of the current study is to examine how nonmodifiable sociodemographic, disease, appointment, management, and survey factors correlate with provider rating. This was a retrospective cross-sectional study conducted on 29 857 patient Clinician and Group Consumer Assessment of Healthcare Providers and Systems surveys collected from January 2017 to January 2019 at a tertiary eye center. We included surveys of patients aged 18 years or older, who answered at least 4 of 6 subfield questions, and completed the survey within 90 days of the appointment. The main outcome was the odds of receiving top box score (TBS) of 10/10 on the survey question regarding overall provider rating. The results showed that the variables with higher odds of TBS included higher overall appointment attendance (odds ratio [OR]: 2.66 [95% CI: 1.23-5.75], P = .013); older patient age (OR 2.44 [95% CI: 2.08-2.87], P < .001]; higher percentage of survey questions completed (OR: 2.02 [95% CI: 1.79-2.27], P < .001); better best corrected visual acuity (OR: 1.85 [95% CI: 1.3-2.64], P = .001); optometry clinic visit (OR: 1.25 [95% CI: 1.15-1.36], P < .001); having procedures (OR: 1.19 [95% CI: 1.04-1.36], P = .013), surgery scheduled (OR: 1.18 [95% CI: 1.03-1.36], P = .020], or refraction done (OR: 1.16 [95% CI: 1.08-1.25], P < .001); being seen by male providers (OR: 1.11 [95% CI: 1.04-1.17], P = .001); and having additional eye testing performed (OR: 1.06 [95% CI: 1.00-1.13], P = .048). Variables associated with lower odds of TBS included longer time to complete survey (OR: 0.42 [95% CI: 0.3-0.58], P = .001); new patient encounter (OR: 0.62 [95% CI: 0.58-0.65], P < .001); and glaucoma (OR: 0.66 [95% CI: 0.59-0.75], P < .001), cornea (OR: 0.79 [95% CI: 0.71-0.87], P < .001), or comprehensive clinic visits (OR: 0.86 [95% CI: 0.79-0.94], P < .001). Thus, nonmodifiable factors may affect the provider rating, and these factors should be studied further and accounted for when interpreting the results of patient experience surveys.

Abstract Background Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. Methods We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at − 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. Results We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbβ3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. Conclusions In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.

Abstract Background Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. Methods Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. Results PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. Conclusions Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.

Category: Bunion Introduction/Purpose: The progression of hallux valgus (HV) deformities results in dislocation of the sesamoids from their position (station) under the plantar surface of the distal first metatarsal. With this dislocation, the crista separating the two sesamoids erodes as the contact of the medial sesamoid with the crista applies pressure with weightbearing. Recently, three dimensional (3D) reconstructions of the metatarsals and first phalanx have demonstrated a means to find a consistently quantify first metatarsal pronation. These same reconstructions can also produce a reliable technique to compute the volumes of the bones involved. The purpose of the current investigation is to examine the relationship of the volume of the crista to pronation and to sesamoid station. Methods: Eleven HV patients and five normal subjects with weightbearing or weightbearing equivalent CT (WBCT) imaging were randomly selected from the senior author’s patients. Pronation was quantified on WBCT scans using 3D reconstructions as described by Campbell et al. (FAI 2018). Crista volume was determined using a line drawn to connect the nadir of each sulcus on either side of the intersesamoidal crista in each slice of the WBCT image (Figure 1). Sesamoid station was also quantified on WBCT scans using the established four point categorization. A linear regression was performed to determine if the volume of the crista was associated with the pronation angle. The sesamoid station was simplified into two categories - mild medial sesamoid subluxation (less than 50% of the medial sesamoid was lateral to the nadir of the crista) and severe medial sesamoid subluxation - and crista volume between these two groups was compared using a t-test. Results: The regression of crista volume against first metatarsal pronation angle did not show statistical significance (P=0.94, r2=0.03). The mean crista volume in the mild medial sesamoid subluxation group was 156(+-47, range 72 - 231)mm3. The mean crista volume in severe medial sesamoid subluxation was 95 (SD 39, range 35 - 160) mm3. The t-test using simplified sesamoid station to compare crista volumes found that the mean crista volume in the mild medial sesamoid subluxation group was statistically significantly greater the than the mean crista volume in the severe sesamoid subluxation group (P=0.01). Conclusion: In HV, it has been hypothesized that the medial sesamoid erodes the crista resulting in arthritis. This is often overlooked as a source of pain in these patients. Our study found that pronation of the first metatarsal was not correlated with crista volume suggesting that pronation does not affect erosion of the crista. Instead, our results are the first to demonstrate that medial sesamoid subluxation as determined from sesamoid station results in erosion of the crista. This supports the hypothesis that sesamoid subluxation, arthritis, and crista erosion are important components of the HV deformity.

Category: Bunion; Other Introduction/Purpose: In hallux valgus (HV), first metatarsal pronation is increasingly recognized as an important aspect of the deformity. Weightbearing CT (WBCT) scans have allowed investigators to quantify pronation of the first metatarsal. Yamaguchi et al. (J Orthop Sci 2015) proposed that pronation of the first metatarsal can be estimated by looking at the shape of the lateral aspect of the first metatarsal head on weightbearing AP radiographs of the foot, which would provide surgeons with a simple and readily available guide for evaluation of pronation. The purpose of this study was to compare pronation determined from the shape of the lateral head of the first metatarsal on AP weightbearing radiographs in HV patients with pronation calculated from WBCT scans. Methods: Patients were included in this study if they had preoperative (n=22 patients) or 5-month postoperative (n=22 patients) WBCT scans and corresponding weightbearing AP radiographs of the affected foot. Pronation on weightbearing AP radiographs was grouped into four groups 0–9°, 10–19°, 20–30°, and >30° as described by Wagner and Wagner (Foot Ankle Clin 2018) by two independent observers. Pronation of the first metatarsal on WBCT scans was measured using a technique developed by Campbell et al. (Foot Ankle Int 2018), which calculates pronation of the first metatarsal in reference to the second metatarsal using a 3D CAD model, and using the alpha angle as described by Kim et al. (Foot Ankle Int 2015) and was categorized into the same four groups described for the radiographs. Weighted kappa coefficients (k) were used to determine interobserver reliability and agreement between pronation groups on radiographs and WBCT scans. Intraclass correlation coefficients were used to determine reliability of the alpha angle measurements on WBCT scans. After dividing patients into plain radiograph pronation groups, differences in mean WBCT pronation of the first metatarsal was compared using Kruskal-Wallis tests. Results: Agreement between the two observers for preoperative and postoperative pronation on radiographs was moderate (k=.529,P 0.80, P30° (n=2), mean pronation calculated from WBCT scans using a 3D CAD method was 21.1°, 25.2°,and 20.9°, respectively (P=.752), and mean pronation calculated using the alpha angle was 13.2°, 15.8°, and 22.3°, respectively (P=.308). Postoperatively, in the plain radiograph pronation groups of 0-9° (n=9), 10-19° (n=6), and 20-29° (n=7), mean pronation calculated from WBCT scans using a 3D CAD method was 22.3°, 22.5°, and 21.0°, respectively (P=.976), and mean pronation calculated using the alpha angle was 3.1°, 5.7°, and 6.4°, respectively (P=.252). Conclusion:: Pronation of the first metatarsal measured on weightbearing AP radiographs using the lateral first metatarsal head had only fair to moderate interobserver agreement and did not statistically significantly agree with pronation measured on WBCT scans using either a 3D CAD model or the alpha angle. Additionally, mean pronation on WBCT scans did not significantly differ by any magnitude between the plain radiograph pronation groups, which indicates that there was no association between pronation measured on WBCT scans and plain radiographs. These results suggest that surgeons should use caution when trying to derive first metatarsal pronation from AP weightbearing radiographs for surgical planning purposes.

Optical coherence angiography (OCTA) is a noninvasive technique that has been introduced in recent years to detect ophthalmological pathology. The growing usage of OCTA to detect retinal abnormalities can be attributed to its advantages over the reference-standard fluorescein angiography (FA), although both of these techniques can be used in association. OCTA's advantages include its dye independency, its ability to produce depth-resolved images of retinal and choroidal vessels that yield images of different vascular layers of the retina, and the better delineation of the foveal avascular zone. OCTA's disadvantages include the lack of normalized patient data, artefactual projection issues, and its inability to detect low-flow lesions or pathologic conditions. Different OCTA platforms use unique algorithms to detect microvasculature, which are implemented in both spectral-domain (SD) and swept-source (SS) OCT machines. Microvascular changes in retinal vein occlusions (RVOs) are visible in both the superficial and deep capillary networks of the retina in OCTA. These visualizations include a decrease in foveal and parafoveal vascular densities, non-perfusion areas, capillary engorgement and telangiectasias, vascular tortuosity, microaneurysms, disruption of the foveal perivascular plexus, and formation of collateral vessels. The restricted field of view and inability to show leakage are important limitations associated with the use of OCTA in RVO cases. In this article, we present a brief overview of OCTA and a review of the changes detectable in different slabs by OCTA in RVO cases published in PubMed and Embase.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterised by chronic joint inflammation, leading to functional disability and increased risk of premature death. Clinical practice guidelines (CPGs) are expected to play a key role in improving management of RA, across the different phases of the disease course. Since new evidence has become available, the Italian Society for Rheumatology (SIR) has been prompted to update the 2011 recommendations on management of RA. The framework of the Guidelines International Network Adaptation Working Group was adopted to identify, appraise (AGREE II), synthesize, and customize the existing RA CPGs to the Italian healthcare context. The task force consisting of rheumatologists from the SIR Epidemiology Research Unit and a committee with experience in RA identified key health questions to guide a systematic literature review. The target audience includes physicians and health professionals who manage RA in practice, and the target population includes adult patients diagnosed as having RA. An external multi-disciplinary committee rated the final version of the CPGs. From the systematic search in databases (Medline, Embase) and grey literature, 6 CPGs were selected and appraised by two independent raters. Combining evidence and statements from these CPGs and clinical expertise, 8 (Management) +6 (Safety) recommendations were developed and graded according to the level of evidence. The statements and potential impact on clinical practice were discussed and assessed. These revised recommendations are intended to provide guidance for the management of RA and to disseminate the best evidence-based clinical practices for this disease.

Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

A linear transformer driver (LTD) generator capable of delivering up to 0.9 MA current pulses with 160 ns rise time has been assembled and commissioned at University of California San Diego. The machine is an upgrade of the LTD-III pulser from Sandia National Laboratories, consisting of 40 capacitors and 20 spark gap switches, arranged in a 20-brick configuration. The driver was modified with the addition of a new trigger system, active premagnetization of the inductive cores, a vacuum chamber with multiple diagnostic ports, and a vacuum power feed to couple the driver to plasma loads. The new machine is called compact experimental system for Z-pinch and ablation research (CESZAR). The driver has a maximum bipolar charge voltage of ±100 kV, but for reliability and testing, and to reduce the risk of damage to components, the machine was operated at ±60 kV, producing 550 kA peak currents with a rise time of 170 ns on a 3.5 nH short circuit. While the peak current is scaled down due to the reduced charge voltage, the pulse shape and circuit parameters are close to the results of the cavity and power feed models but suggest a slightly higher inductance than predicted. The machine was then used to drive wire array Z-pinch and gas puff Z-pinch experiments as initial dynamic plasma loads. The evolution of the wire array Z pinch is consistent with the general knowledge of this kind of experiment, featuring wire ablation and stagnation of the precursor plasma on axis. The gas puff Z pinches were configured as a single, hollow argon gas shell, in preparation for more structured gas puff targets such as multispecies, multishell implosions. The implosion dynamics agree generally with 1D magnetohydrodynamics simulation results, but large zippering and magneto-Rayleigh-Taylor instabilities are observed. The CESZAR load region was designed to accommodate many load types to be driven by the machine, which makes it a versatile platform for studying Z-pinch plasmas. The completion of the CESZAR driver allows plasma experiments on energy coupling from LTD machines to plasma loads, instability mitigation techniques and magnetic field distributions in Z pinches, and interface dynamics in multispecies implosions.

Joint involvement is a common manifestation in systemic lupus erythematosus (SLE). According to the SLE disease activity index 2000 (SLEDAI-2K), joint involvement is present in case of ≥2 joints with pain and signs of inflammation. However this definition could fail to catch all the various features of joint involvement. Alternatively the Swollen to Tender joint Ratio (STR) could be used. This new index, which was originally proposed for rheumatoid arthritis (RA) patients, is based on the count of 28 swollen and tender joints. Our study is, therefore, aimed to assess joint involvement in a SLE cohort using the STR. SLE patients with joint symptoms (≥1 tender joint) were enrolled over a period of one month. Disease activity was assessed by SLEDAI-2K. We performed the swollen and tender joint count (0-28) and calculated the STR. Depending on the STR, SLE patients were grouped into three categories of disease activity: low (STR1.0). We also calculated the disease activity score based on a 28-joint count and the erythrocyte sedimentation rate (DAS28-ESR). We enrolled 100 SLE patients [F/M 95/5, mean±standard deviation (SD) age 46.3±10.6 years, mean±SD disease duration 147.1±103.8 months]. The median of tender and swollen joints was 4 (IQR 7) and 1 (IQR 2.5), respectively. The median STR value was 0.03 (IQR 0.6). According to the STR, disease activity was low in 70 patients, moderate in 23 and high in 7. A significant correlation was identified between STR values and DAS28 (r=0.33, p=0.001). The present study suggests a correlation between STR and DAS28, allowing an easier and faster assessment of joint involvement with the former index.

Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice.Methods: Metabolic parameters, cardiac function, arterial pressure (AP), autonomic, hormonal, inflammatory, and oxidative stress markers were evaluated in 12-weeks female wild-type (WT group) and ob/ob mice (OB group).Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF) and AP were similar between groups; however, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissues; decreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress.Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous clinical manifestations involving virtually the entire body. The pain in SLE can have different causes. The SLE classification criteria include mainly the musculoskeletal manifestations of pain, which are commonly reported as initial symptoms of SLE, such as arthralgia, arthritis and/or myalgia. Chronic widespread pain, which is typical of fibromyalgia (FM), is frequently associated with SLE. The aim of this review is to describe widespread pain and fatigue in SLE, and the association of SLE and FM. Although secondary FM is not correlated with the disease activity, it may interfere with the daily activities of SLE patients. Therefore it is necessary to identify its symptoms and treat them promptly to improve the quality of life of patients. In conclusion, it is essential to identify the origin of pain in SLE in order to avoid dangerous over-treatment in patients with co-existing widespread pain and FM.