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Catalin O Codreanu,1 Nemanja Damjanov2 1Rheumatology Department, Center of Rheumatic Diseases, Bucharest, Romania; 2Institute of Rheumatology, School of Medicine, University of Belgrade, Belgrade, SerbiaAbstract: Over the past decade, the use of biologics has significantly changed the management of rheumatoid arthritis (RA). Biologics selectively target components of the immune system, resulting in better disease control. However, the growing use of biologics in RA has increased safety concerns among rheumatologists. Randomized controlled trials (RCTs) and registries are the most reliable sources of clinical safety data. Although safety data from RCTs provide certain insights into the clinical safety profile of an agent, strict constraints in study design (eg, exclusion criteria and restrictive treatment protocols) often do not accurately reflect possible safety issues in the use of the agent, either in the clinical setting or over long-term treatment. Registries, on the other hand, are not restrictive regarding patient enrollment, making them more reliable in evaluating long-term safety. A number of registries have been established globally: in Europe, the United States, and Asia. However, the availability of registry data from Eastern Europe is lacking. The notable exceptions so far are registries from the Czech Republic (ATTRA, a registry of patients treated with anti-tumor necrosis factor-alpha drugs) and Serbia (National registry of patients with rheumatoid arthritis in Serbia [NARRAS]). The current report provides an overview of safety data with biologics in RA from RCTs and registries. Availability of regional safety data from Eastern Europe is of great importance to its clinicians for making evidence-based treatment decisions in RA. Keywords: biologic therapy, biologic drugs, adverse events, infections, pregnancy, malignancies

Objective: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years' duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets.Method: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud's SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud's phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31-59, and ≥ 60 years. We performed descriptive and bivariate analyses.Results: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud's.Conclusion: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To validate ultrasonographic criteria for examination of the major salivary glands in the diagnosis of primary Sjögren's syndrome (SS). Method: A total of 209 consecutive patients with rheumatic diseases were selected according to the American-European Consensus Group (AECG) classification criteria for SS. One hundred and fifteen patients had primary SS, 44 had secondary SS, and 50 had sicca symptoms, and 36 subjects served as asymptomatic controls. This cohort was analysed for size, echogenicity, parenchymal inhomogeneity, focal changes, and posterior borders of the major salivary glands by ultrasonography (US). A novel US score for parenchymal inhomogeneity (0-12) was assigned and its diagnostic accuracy evaluated. Results: Ultrasonographic abnormalities of salivary glands were detected in 107/115 (93.0%) patients with primary SS, in 12/44 (27.3%) with secondary SS, in 25/50 (50.0%) with sicca symptoms, and in 4/36 (11.1%) asymptomatic controls. Area under the receiver operating characteristic curve (AUC-ROC) for US inhomogeneity score was highly significant [0.96 +/- 0.01; 95% confidence interval (CI) 0.94-0.99, p < 0.000] for primary SS, with a sensitivity to specificity ratio of 91/83 for parotid and 93/90 for submandibular glands. Setting the cut-off US inhomogeneity score at 6 resulted in the best ratio of specificity (90.0%) to sensitivity (95.1%), with a positive predictive value of 72% and a negative predictive value of 96%. A US inhomogeneity score >or= 6 was closely correlated with positive biopsy (p < 0.000) and scintigraphy findings (p < 0.000). Conclusions: We demonstrate the high diagnostic value of a novel US score for parenchymal inhomogeneity (0-12) that could serve as a useful single US criterion in the evaluation of salivary gland involvement in primary SS. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA). METHODS: Two 12-week, double-blind, placebo-controlled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments. RESULTS: The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%). CONCLUSION: The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA. [ABSTRACT FROM AUTHOR]

Abstract: Objective: to assess the frequency of risk factors for gastro-intestinal (GI) bleeding in patients already using NSAID''s prescribed in general practice (GP). Methods: 150 doctors in GP health institutions were collecting data in 2005, and 2006 about risk factors for gastro-intestinal (GI) bleeding in their patients using NSAID''s. Following risk factors were included: smoking, corticosteroid therapy, regular aspirin therapy, anticoagulant therapy, history of GI problems and excess alcohol consumption. Research technique: Face-to-face interview, in health institution. Over the period of one week, GPs kept records of treating patients using NSAID''s. Duration of questionnaire: 8-10 minutes. Descriptive statistic methods were used for data analyzes. Results: Age distribution of patients was: under 30y 373 (3.8%) patients, 30-45y 1521 (15.7%) patients, 46-60y 3655 (37.6%) patients, over 60y 3926 (40.4%) patients out of total 9704 patients - 4209 (43.4%) men, and 5495 (56.6%) women. The reason for use of NSAID''s was: osteoarthritis in 5301 (54.6%) patients, arthritis in 2032 (20.9%) patients, other in 2371 (24.4 %) patients. Total number of patients with risk factors for GI bleeding was 7809 (80.5%).The frequency of particular risk factor was as follows: smoking in 2594 (33.2%) patients, history of GI problems in 1812 (23.2%) patients, regular aspirin therapy in 1329 (17%) patients, anticoagulant therapy in 662 (8.5%) patients and excess alcohol consumption in 587 (7.5%) patients. Conclusions: Total number of patients with risk factors for GI bleeding was extremely high - 7809 (80.5%), smoking being the most widespread risk factor (33.2%) followed by history of gastro-intestinal problems. Most of the patients were over age of 60 (40.4%), which is the independent risk factor for GI bleeding. High frequency of GI risk factors in population of patients treated in general practice emphasize the need for possible protective measures (use of COX-2 selective drugs, concomitant use of NSAID''s and inhibitors of proton pump-PPI) to reduce the risk for GI bleeding. [Copyright &y& Elsevier]

An abstract of the conference paper "Influence of TNFα-308 and T676G TNF-RII polymorphism on response to etanercept and possibility to discontinue treatment," by G. Susic and colleagues, presented at the Pediatric Rheumatology European Society (PReS) Congress held in Belgium is presented.

An abstract of the conference paper "DNase I levels and disease outcome in JIA patients treated with etanercept," by N. Damjanov and colleagues is presented.

An abstract of the conference paper "Does childhood health assessment questionnaire can predict outcome of patients with juvenile idiopathic arthritis?," by G. Susic and colleagues is presented.

An abstract of the conference paper "Epigenetic modulation with oral histone deacetylase (HDAC) inhibitor as a new treatment option in JIA," by J. Vojinovic and colleagues is presented.

Aims: Data regarding the treatment of hip osteoarthritis (OA) with collagen-based extracellular bio-scaffolds are lacking. We evaluated the treatment of hip OA with ultrasound guided intraarticular injections of Collagen-based Medical Device (CMD)., Material and Methods: Forty-four patients with Kellgren-Lawrence grade (KLG) I or II were selected, and 20/44 randomly selected patients (CMD group), were treated with 2 weekly consecutive ultrasound guided intraarticular injections of CMD (MD-HIP, Guna S.p.a. Milan, Italy). An additional 24/44 patients were treated with oral non-steroidal anti-inflammatory drugs (NSAIDs) daily (NSAIDs group). Clinical assessment, X-rays and ultrasound evaluation were performed at baseline, and after 1 month in both groups, and after 3 months in the CMD group. Outcome measures were general pain VAS (0-10), the whole WOMAC score, and the WOMAC specific subscores., Results: CMD and NSAIDs group were homogenous for age, gender, VAS pain and WOMAC scores. The CMD group had significant improvement of the VAS pain (p<0.0001), global WOMAC score (p<0.0001) and WOMAC function (p<0.0001) from baseline to the 1st month, with further improvement from the 1st to the 3rd month (p<0,001; p<0.01; p<0.03, respectively). Significant improvement in WOMAC pain (p<0.0001) and WOMAC stiffness (p<0.0001) was detected at 1st month, with no significant change at 3rd month. In the NSAIDs group significant improvement in WOMAC function was detected after 1 month (p=0.021) only. No adverse events were recorded in the CMD and NSAIDs group., Conclusion: The ultrasound guided intraarticular hip injections of CMD resulted in significant improvement in VAS pain and WOMAC scores compared to treatment with oral NSAIDs.

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD., Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t 0 ) and after 12 (±4) (t 1 ) and 24 (±4) (t 2 ) months., Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t 2 . Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t 2 ( p = 0.0031). Neither the mean t 0 to t 1 change (Δ) of DLCO nor the mean t 0 to t 1 FVCΔ predicted the appearance of ILD at t 2 . Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t 0 DLCO < 80%, stronger than that of FVC < 80%., Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Purpose: Capecitabine-Temozolomide (CapTem) is an oral chemotherapy regimen for NETs. Both drugs are radiosensitizers. Integrating CapTem and Y90 transarterial radioembolization (TARE) in patients with grade 2 neuroendocrine tumor (NET) liver metastases achieved an encouraging objective response rate (ORR) and progression-free survival (PFS) in a feasibility study. This study expands that report to a larger cohort with longer follow-up., Methods: Therapy consisted of monthly cycles of capecitabine 600 mg/m 2 twice daily for 14 days and temozolomide 150-200 mg/m2 on day 10-14. Simulation angiography was performed during the initial cycle. The dominant lobe was treated with 90 Y-resin microspheres using BSA dosimetry on day 7 of the second cycle of CapTem. Patients with bilobar disease had the other lobe treated on day 7 of the third or fourth cycle. CapTem was continued until progression or intolerance. Clinical and laboratory assessment was done monthly and imaging every 3 months., Results: 35/37 patients completed the prescribed regimen. Primary sites of disease were pancreas (16), lung (10), gut (7) and unknown (4). Mean duration of CapTem was 12 months (range, 4-32 months). ORR in the liver was 72% with a disease control rate of 100%. Median PFS was 36 months (95% CI, 25-45 months). Median overall survival was 41 months (95% CI, 24-87 months) from initiation of CapTemY90 therapy and 130 months (95% CI, 56-172 months) from initial diagnosis., Conclusion: Chemoradiation with CapTem and TARE provided durable control of G2 NET liver metastases for substantially longer than expectations for embolotherapy or chemotherapy alone., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Objective: This study was performed to assess the impact of autologous conditioned serum (ACS) when added to preceding intra-articular glucocorticoid therapy on pain, function, and quality of life outcomes over 24 weeks., Methods: In this single-center, randomized controlled trial involving 40 patients with advanced knee osteoarthritis (Kellgren-Lawrence grades III and IV), ACS or saline placebo was injected after 40 mg triamcinolone acetonide (TA) intra-articular injection. Numerical rating scale (NRS) pain scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) assessments were conducted at baseline and at weeks 3, 6, 12, and 24. The primary endpoint was the change in KOOS Pain at 24 weeks. Patient safety events were also monitored., Results: At week 24, TA + ACS significantly improved KOOS Pain, Symptoms, Activities of Daily Living, Quality of Life, and KOOS Sport scores. TA + ACS also outperformed TA + placebo in NRS pain scores (average and maximum intensity) at week 24 and NRS pain score (at rest) at weeks 12 and 24. The TA injection followed by ACS or placebo was well-tolerated., Conclusion: ACS adds long-term pain relief and functional improvement to the short-term pain relief provided by glucocorticoids.

Purpose: Telegenetics services can expand access to guideline-recommended cancer genetic testing. However, access is often not distributed equitably to all races and ethnicities. We evaluated the impact of an on-site nurse-led cancer genetics service in a diverse Veterans Affairs Medical Center (VAMC) oncology clinic on likelihood of germline testing (GT) completion., Methods: We conducted an observational retrospective cohort study of patients who were referred for cancer genetics services at the Philadelphia VAMC between October 1, 2020, and February 28, 2022. We evaluated the association between genetics service (on-site v telegenetics) and likelihood of GT completion in a subcohort of new consults, excluding patients with prior consults and those referred for known history of germline mutations., Results: A total of 238 Veterans, including 108 (45%) seen on site, were identified for cancer genetics services during the study period, with the majority referred for a personal (65%) or family (26%) history of cancer. In the subcohort of new consults, 121 Veterans (54% self-identified race/ethnicity [SIRE]-Black), including 60 (50%) seen on site, were included in the analysis of germline genetic testing completion. In a univariate analysis, patients who were seen by the on-site genetics service had 3.2-fold higher likelihood of completing GT (relative risk, 3.22; 95% CI, 1.89 to 5.48) compared with the telegenetics service. In multivariable regression analysis, the on-site genetics service was associated with higher likelihood of GT completion, but this association was only statistically significant in SIRE-Black compared with SIRE-White Veterans (adjusted RR, 4.78; 95% CI, 1.53 to 14.96; P < .001; P -interaction of race × genetics service = .016)., Conclusion: An on-site nurse-led cancer genetics service embedded in a VAMC Oncology practice was associated with higher likelihood of germline genetic testing completion than a telegenetics service among self-identified Black Veterans.

Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc., Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database., Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023., Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers)., Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up., Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.