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Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol ⩾240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3×–<5× upper limit of normal (1.0% vs 2.5%), respectively. Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed. Trial registration number: NCT00109408

Background:Sjögren’s disease (SD) patients have some specific features that could make them even more prone to SARS-CoV-2 infection (mucosal dryness, altered exocrine gland excretions), but the data are limited.Objectives:The aim of our study was to determine clinical and epidemiological characteristics of SARS-CoV-2 infection in a well-defined cohort of patients with SD.Methods:Our cohort consisted of patients diagnosed with SD based on the ACR/EULAR 2016 classification criteria1 between January 2016 and December 2019. Patients were regularly followed at our secondary/tertiary centre. In March 2022 retrospective reviews of patient’s medical record were performed, searching for any information about the confirmed SARS-CoV-2 infection in the period between March 2020 and February 2022. All patients with a confirmed SARS-CoV-2 infection were contacted by phone to fulfill a questionnaire regarding their infection course (mild disease or severe disease - latter defined as need of hospitalization, thrombotic events, due to SARS-CoV-2 infection or death). Descriptive statistics were used to explore the studied population by using SPSS version 27.Results:In our cohort of 169 SD patients (94% female, median age 60.5 [IQR: 51-69, range: 23-88]) 66 patients had at least one SARS-CoV-2 infection documented (39 %), in most patients (48/66, 72.7 %) the infection course was mild. Five patients (7.5%) had severe infection requiring hospitalization (3 patients between March and December 2021 and 2 patients in early 2022). There were no deaths and thrombotic events due to infection. The comparison of characteristics of SARS-CoV-2 infected group to SARS-CoV-2 negative group (Table 1) showed that males and younger patients were more at risk for SARS-CoV-2 infection. We found no differences in unstimulated salivary flow test, Schirmer’s test, Rose Bengal test or baseline ESSDAI between SD patients with and without SARS COV-2 infection.Conclusion:Almost 40 % of our SD patients had at least one SARS-CoV-2 infection during the 24 month observation period. Younger males were at greater risk of COVID-19, but we did not find any association between the objective severity of mucosal dryness nor baseline systemic disease activity and the risk of SARS-COV-2 infection.REFERENCES:[1] Shiboski CH, et al. Arthritis Rheumatol 2017;69:35–45.Table 1. Clinical and laboratory characteristics of SD patients with and without SARS-CoV-2 infectionBMI – Body Mass Index, USF – Unstimulated Salivary Flow, CRP – C-reactive protein, ESR – Elevated Sedimentation Rate, aENA – Anti-Extractable Nuclear Antigen Antibody, RF – Rheumatoid Factor, ESSDAI – EULAR Sjögren’s syndrome disease activity indexAcknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundThe inflammation of thyroid arteries (ThA) is not commonly considered and investigated in giant cell arteritis (GCA).ObjectivesTo estimate the frequency of the superior and/or inferior ThA involvement as detected by Colour Doppler Sonography (CDS).MethodsWe conducted a prospective single centre study between 1 October 2013 and 30 September 2017. The CDS of superior and inferior ThA was performed in all newly diagnosed, treatment naive GCA patients in addition to the routinely evaluated temporal, facial, occipital and large supraaortic arteries. The superior and inferior ThA were identified at their respective anatomical locations in close proximity to the thyroid gland and examined using the standard Doppler settings for temporal arteries. Arteries were evaluated in two planes for the highly specific halo sign. Laboratory thyroid function tests consisted of TSH, T3 and T4 measurements at the time of GCA diagnosis (prior to any steroid therapy). Characteristics of GCA cases with inflamed ThA were explored and compared to the GCA group without ThA involvement.ResultsDuring the 48 months we performed the CDS of the multiple arteries in 124 consecutive GCA patients (median age 74.7 (IQR 66.5–79.1) years, 65% female). We observed the halo sign on either superior or inferior ThA in 11 (8.9%) cases. All the patients with ThA involvement also had CDS signs of temporal artery involvement, which was confirmed by temporal artery biopsy in all 11 cases. There was a positive trend for correlation between fever (≥38°C) and/or dry cough in the patients with ThA involvement (fever: RR 2.99, CI 0.98–9.06, p=0.07; dry cough: RR 2.73, CI 0.89–8.3, p=0.10). Four patients reported symptoms consistent with thyroid gland pathology. None of the patients with ThA involvement had symptoms of polymyalgia rheumatica. No correlation was found with other clinical and demographic characteristics, including weight loss, headache, jaw claudication and visual disturbances.Sixteen out of 124 GCA patients (12.9%) had a history of thyroid dysfunction (11 hypothyroidism, 1 hyperthyroidism, 1 euthyroid goitre; 3 patients had thyroid surgery because of either goitre or suspected malignancy). In 2/16 patients we also found CDS signs of ThA involvement, yet the thyroid function tests were normal at the time of GCA diagnosis in these patients. Laboratory signs of thyroid dysfunction were found in 3/11 (27.2%) patients with ThA involvement (2 latent hyperthyroidism, 1 latent hypothyroidism), none of these patients had previous history of thyroid disease.ConclusionsIn our incipient GCA cohort, a tenth of all patients had ultrasonographic signs of ThA involvement. To the best of our knowledge, this is the first study that systematically assessed the ThA involvement.Disclosure of InterestNone declared

BackgroundGlucocorticoids (GC) have been the mainstay treatment in giant cell arteritis (GCA) for decades. Recently tocilizumab and abatacept have been proven to be effective alternatives to glucocortiocids. However, not all GCA patients are eligible for a biologics.ObjectivesWe aimed to evaluate the role of leflunomide (LEF) as a steroid sparing agent in GCA.MethodsThis prospective observational study included newly diagnosed GCA patients followed at least 48 weeks at a single secondary/tertiary rheumatology centre.Patients were treated with GC in line with the EULAR recommendations.1 In short, patients with uncomplicated GCA initially received oral methylprednisolone (MP) 32–48 mg qd, while those with ischaemic complications or large vessel disease first received MP 250 mg on 3 consecutive days intravenously, followed by oral MP. MP tapering was started 2–4 weeks after treatment initiation slowly to 4 mg qd which was continued for at least 6 months. At week 12, LEF 10 mg qd was recommended as an add-on therapy to those GCA patients without contraindications for it. The final decision to add LEF was patient dependent. Follow-up visits with predetermined clinical and laboratory tests were performed 4, 12, 24, 48, 96 and 144 weeks after diagnosis. In patients who relapsed during the MP tapering unscheduled visits were arranged and treatment was adjusted (GC dose was increased and LEF 10 mg or LEF dose increase to 20 mg or alternative steroid sparing agent in case of LEF ineffectiveness recommended). The number of relapses and a cumulative GC dose during follow-up were recorded.ResultsBetween July 2014 and December 2016 we identified 76 (65.8% female, median (IQR) age 73.7 (66.1–78.8) years) new GCA cases with a follow-up of at least 48 weeks (median (IQR) 7551–104 weeks). 30/76 patients (39.5%) received LEF at W12 (“LEF” group), the others continued with GC only. During the follow-up 22 patients relapsed, 4 in “LEF” group (13.3%) and 18 (39.1%) in “GC only” group. The difference was statistically significant (p=0.02; NNT 3.9 (95%CI 2.2–17.4)). Furthermore, 17/30 GCA cases (56.7%) in “LEF” group managed to stop GC at W48 (with 1 relapse (5.9%) shortly afterwards), but none in GC only group. Patients tolerated LEF relatively well. Adverse events (AEs) were usually mild. 8/30 patients (26.7%) discontinued LEF (1 due to ineffectiveness and 7 due to one/more AEs – hair loss developed in 4/7 cases, diarrhoea in 2/7 patients, weight loss in 2/7 cases, and elevated transaminases in 1/7). The occurrence of infections requiring antibiotics and/or hospital admission was lower in LEF group compared to “GC only” group (10% vs. 26.5%).ConclusionsWe found in our prospective observational study in GCA a steroid sparing action and a rather good tolerability of LEF.Disclosure of InterestNone declared

BackgroundPredictors of severity of visceral involvement in acute adult IgA vasculitis (IgAV) are poorly recognised.ObjectivesThe aim of our study was to evaluate the role of smoking and extension of skin lesions on the visceral manifestations of acute adult IgA vasculitis.MethodsWe analysed medical records of adult, histologically proven IgAV cases, diagnosed at our secondary/tertiary rheumatology centre between 1 January 2010 and 31 December 2017. Purpura was defined as generalised when skin lesions extended above the waistline. Gastrointestinal (GI) disease was considered severe in case of bloody diarrhoea, ileus or bowel perforation. Renal disease was defined as severe when nephritic syndrome with acute renal failure or nephrotic syndrome developed.ResultsDuring the study period we identified 230 incident IgAV cases (57.8% males, median (IQR) age 64.8 (45.6–77.3) years). Ninety-eight (42.6%) patients were smokers (56 past and 42 current). Skin, joint, GI, renal and involvement were present in 230 (generalised purpura in 114 (49.6%), necrotizing in 108 (47.0%)), 93 (40.4%), 70 (30.4%; severe in 17) and 102 (44.3%; severe in 27) patients, respectively. Smoking was associated with renal disease (RR 1.3 (95%CI 1.0–1.8)) and its severity (RR 3.2 (95%CI 1.5–7.0)), but not with GI involvement or its severity. Generalised purpura was associated with GI involvement (RR 2.9 (95%CI 1.8–4.7) and its severity (RR 3.3 (95%CI 1.1–9.8)), as well as with renal involvement (RR 1.4 (95%CI 1.0–1.9)). Data of combined influence of smoking and purpura extension on visceral involvement are presented in table 1. The risk of severe renal involvement in IgAV was the highest in ever-smoker with generalised purpura (RR 8.1 (95%CI 1.9–34.7) in comparison to IgAV non-smoker with localised purpura).Table 1 The influence of smoking and purpura extension on visceral involvement in IgAVConclusionsSmoking and generalised purpura were associated with visceral involvement in adult IgAV.Disclosure of InterestNone declared

Immunoglobulin A vasculitis (IgAV) is an immune complex, small vessel vasculitis with dominant IgA deposits in vessel walls, predominantly affecting the pediatric population. However, adults frequently have more severe gastrointestinal tract (GIT) and renal involvements as compared to children. Our aim was to study serological and cellular biomarkers to support clinicians in their diagnosis and the course of IgAV in adult patients. This cross-sectional study included 62 adult IgAV patients and 53 healthy blood donors (HBDs). Demographic and clinical data, as well as routine laboratory tests, were meticulously analyzed. Serum levels of IL-1β, IL-2, IL-6, IL-8, IL-9, IL-10, IL-17A, IL-23, TNF-α and serum amyloid A (SAA) were measured. Percentages of neutrophils, lymphocytes, and monocytes with neutrophil expression of L-selectin and integrin αM were determined by flow cytometry. SAA (12-fold), IL-6 (3-fold), IL-8 (2-fold), and TNF-α (2-fold) were significantly elevated in sera of adult IgAV patients compared to HBDs. There was a 16% elevation in neutrophils in IgAV patients, with IgAV neutrophils showing significantly higher CD62L surface expression. IgAV patients with GIT involvement exhibited elevated numbers of leukocytes, neutrophils, and neutrophil/lymphocyte (NLR), but lower neutrophil CD11b expression, as compared to IgAV patients without GIT. IgAV patients exhibit a low–medium grade inflammatory, neutrophil-driven response. Patients with GIT can be distinguished by their elevated NLR.

Upper-arm evaluation including shoulder motion in physiotherapy has no three-dimensional tool for an arm-functioning evaluation, which hampers an uniform, objective comparison. Human shoulder complex models suffer from lack of shoulder girdle kinematic data. A kinematic shoulder-complex model with six degrees of freedom is proposed as the composition of the inner joint representing the shoulder-girdle joints and outer joint representing the glenohumeral joint. The outer shoulder joint has three perpendicular rotations: adduction/abduction, retroflexion/flexion and internal/external rotation of the humerus. The inner shoulder joint has two rotations, depression/elevation and retraction/protraction, and one translation, which are all dependent on the elevation angle of the humerus. The human arm-reachable workspace that represents the area within reach of the wrist is calculated on the basis of the shoulder-complex model and the additional elbow-joint direct kinematics. It was demonstrated that cross-sections of the calculated workspace are in agreement with the measured arm-reachable workspace in all three anatomical planes. The arm-reachable workspace volume and graphics were calculated and a comparison of the arm's workspaces during a patient's shoulder treatment was made. The obtained numerical and graphical arm-reachable workspaces can be used for arm-functioning evaluations in rehabilitation and ergonomics.

Background. RA patients have a higher incidence of cardiovascular diseases compared to the general population. Serum amyloid A (SAA) is an acute-phase protein, upregulated in sera of RA patients. Aim. To determine the effects of medications on SAA-stimulated human coronary artery endothelial cells (HCAEC). Methods. HCAEC were preincubated for 2 h with medications from sterile ampules (dexamethasone, methotrexate, certolizumab pegol, and etanercept), dissolved in medium (captopril) or DMSO (etoricoxib, rosiglitazone, meloxicam, fluvastatin, and diclofenac). Human recombinant apo-SAA was used to stimulate HCAEC at a final 1000 nM concentration for 24 hours. IL-6, IL-8, sVCAM-1, and PAI-1 were measured by ELISA. The number of viable cells was determined colorimetrically. Results. SAA-stimulated levels of released IL-6, IL-8, and sVCAM-1 from HCAEC were significantly attenuated by methotrexate, fluvastatin, and etoricoxib. Both certolizumab pegol and etanercept significantly decreased PAI-1 by an average of 43%. Rosiglitazone significantly inhibited sVCAM-1 by 58%. Conclusion. We observed marked influence of fluvastatin on lowering cytokine production in SAA-activated HCAEC. Methotrexate showed strong beneficial effects for lowering released Il-6, IL-8, and sVCAM-1. Interesting duality was observed for NSAIDs, with meloxicam exhibiting opposite-trend effects from diclofenac and etoricoxib. This represents unique insight into specific responsiveness of inflammatory-driven HCAEC relevant to atherosclerosis.

BackgroundAn increased incidence rate of cancer has been reported in adult patients with IgA vasculitis (IgAV). These conclusions are mostly based on observations in severely ill, hospitalised subgroup of patients. Most of the studies allowed for a wide time interval between IgAV and cancer appearance, not necessarily reflecting a causative link.ObjectivesThe aim of our study was to look for the potential association between IgAV and cancer in an unselected adult IgAV population.MethodsWe analysed medical records of prospectively followed, histologically proven adult IgAV cases at our secondary/tertiary rheumatology centre between 1 January 2010 and 30 June 2017, who were followed until 31 December 2017 and lived in a well-defined referral region. We identified cancer as concurrent with IgAV, if the patients had active cancer or a relapse of cancer or newly-diagnosed cancer diagnosed up to 6 months prior or 6 months after IgAV diagnosis. Cancers developing after 6 months of follow up were labelled as unrelated to IgAV. We used appropriate descriptive statistical methods, and the Fisher’s exact and Mann-Whitney U tests to assess differences of clinical characteristics in acute phase of IgAV, between the cancer and non-cancer groups. The national prevalence and age adjusted incidence rates of cancer from a well-defined referral region were obtained from National cancer registry (NCR).ResultsDuring the 90 months of observation we identified 196 new IgAV cases. 2 patients died in the acute disease phase due to vasculitis, and 8 during the first 6 months of follow-up for reasons other than IgAV or cancer. 20 patients were lost to follow-up. The remaining 166 patients (55% male, median (IQR) age 6343–76 years) were followed for a median (IQR) of 2011 - 32 months. At the time of IgAV diagnosis, 6/166 (3.6%) had active, previously diagnosed malignant disease (prostatic cancer in 4, among which one also had cancer of urinary bladder, and sarcoma in 2 patients). In 2/166 patients (1.2%) a new cancer was diagnosed at presentation and in 2/166 (1.2%) during follow-up. One of the patients with an active cancer of urinary bladder, was treated with antibiotics for urinary tract infection prior to IgAV diagnosis, and was also on chemotherapy. The patients with cancer were older (median age (IQR) 8077–83 vs. 6444–77 years; p=0.002) but their presenting features of IgAV, and the initial IgAV treatment did not significantly differ from those without cancer. At the end of the observation period, the prevalence of cancer in our cohort was 6.0%, compared to the 4.8% prevalence of cancer in our general population and the relative risk of cancer in our IgAV cohort was 1.25 (95% CI 0.687–2.29; p=0.461). The age adjusted incidence rate of cancer was 11.4 per 1000 patients per year. The annual age adjusted incidence rate of cancer in our citizens, acquired from NCR, was 8.9 per 1000 adults and the standardised incidence ratio for our IgAV cohort was 1.62 (CI 0.441–4.15; p=0.472).ConclusionsIn our cohort of unselected adult IgAV cases, we did not confirm the previous observations of the association of IgAV, and cancer.Disclosure of InterestNone declared

Autoantibodies against dsDNA are utilized for the diagnosis and prognosis of SLE as they are highly specific and correlate with disease activity/renal involvement. However, different detection methods are used in routine diagnostic laboratories. Farr radioimmunoassay (Farr-RIA) has been designated as the preferred method, since it provides very specific and at the same time quantitative results, enabling follow-up of level variations over time. Using intercalating fluorescent dsDNA dye would enable all the benefits of Farr-RIA without the radioactive material and organic solvents. To develop a modified fluorescent Farr method (Farr-FIA) and compare it to the classical Farr-RIA in regard to laboratory parameters, as well as clinical utility. Assays were tested on sera of 70 SLE patients, 78 other autoimmune patients, and 145 healthy blood donors. DNA for Farr-FIA was isolated from healthy donor, for Farr-RIA, 14C-labeled dsDNA from E. coli was used and mixed with sera in borate-buffered saline, followed by precipitation with saturated ammonium sulfate solution and centrifugation. The supernatant (S) was separated from the precipitate (P), and content of dsDNA was measured with PicoGreen (Invitrogen) in Farr-FIA or radioactive isotope in scintillation solution in Farr-RIA. The results were calculated as a ratio (P-S)/(P+S). Farr-FIA has a diagnostic sensitivity of 53% and diagnostic specificity of 100% (ROC AUC 0.781). Good correlation and agreement were shown between Farr-RIA and Farr-FIA. Also, there is good correlation between Farr-FIA and SLEDAI, comparable to that of Farr-RIA. Farr-FIA differs from Farr-RIA in the changed detection system yielding comparable results and thus could represent a nonradioactive replacement for Farr-RIA.