Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment. AbstractCalprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-a inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.
Background Whether patients with autoimmune rheumatic diseases (ARD) have a higher risk for SARS-CoV-2 infection (COVID-19) and how SARS-CoV-2 pandemic impacts on adherence to therapy has not been fully elucidated. We assessed the rate and clinical presentation of COVID-19, and adherence to therapy in a large cohort of patients with ARD followed-up in a tertiary University-Hospital in Northeast Italy. Methods Between April 9th and April 25th , 2020, after SARS-CoV-2 infection peak, a telephone survey investigating the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), and idiopathic inflammatory myopathies (IIM) was administered. Demographics, disease activity status, therapy, occupational exposure, and adherence to social distancing advise were also collected. Results 916 patients (397 SLE, 182 AAV, 176 SSc, 111 RA, 50 IIM) completed the survey. 148 patients developed at least one symptom compatible with COVID-19 (cough 96, sore throat 64, fever 64, arthromyalgias 59, diarrhea 26, conjunctivitis 18, ageusia/hyposmia, 18). Among the 916 patients, 65 (7.1%) underwent SARS-CoV-2 nasopharyngeal swab (18 symptomatic and 47 asymptomatic), 2 (0.21%) tested positive, a proportion similar to that observed in the general population of the Veneto region. No deaths occurred. 31 patients (3.4%) withdrew ≥1 medication, mainly immunosuppressants or biologics. Adoption of social distancing was observed by 860 patients (93.9%), including 335 (36.6%) who adopted it before official lockdown. Conclusions COVID-19 incidence seems to be similar in our cohort compared to the general population. Adherence to therapy and to social distancing advise was high.
Objectives To demonstrate that unsuccessful treatment optimisation in early disease is associated with difficult-to-treat rheumatoid arthritis (D2T-RA). Methods In this retrospective multicentre cohort study conducted from 09/2021–03/2022, we enrolled individuals fulfilling the 2010 ACR/EULAR RA criteria diagnosed 2000–2019. The outcome was D2T-RA by the EULAR definition. We used robust regression to examine the associations with delay, dose, duration of methotrexate, and discontinuation of glucocorticoids. We tested through multinomial regression which factors were associated with persistent inflammatory refractory RA (PIRRA) or non-inflammatory refractory RA (NIRRA). Sensitivity analysis included a case-control study matching the year of diagnosis. Results We enrolled 48 D2T-RA patients and 145 non-D2T-RA controls. Methotrexate was started within 3 months in 16.7% of D2T-RA vs 33.1% of non-D2T-RA (p= 0.011). Adequate duration of methotrexate was obtained in significantly fewer D2T-RA patients (70.8% vs 85.5%). Glucocorticoids were continued beyond 6 months in a higher proportion of D2T-RA patients (70.8% vs 33.8%, p< 0.001). In multiple regression, treatment delay beyond 3 months (OR 0.3; 95% CI 0.1; 0.9) and non-discontinuation of glucocorticoids after 6 months (OR 4.6; 95% CI 2.2; 9.5) were significantly associated with D2T-RA. Treatment delay was significantly associated with PIRRA only, whilst non-discontinuation of glucocorticoids was significantly associated with PIRRA and NIRRA. Results were replicated in sensitivity analyses. Conclusion Failure to start methotrexate within 3 months and not being off glucocorticoids within 6 months are early predictive features of D2T-RA.
BackgroundA definition of difficult-to-treat/refractory rheumatoid arthritis (RA) (RRA) has not been established yet, nevertheless, RRA is commonly associated with the resistance to multiple bDMARDs [1,2,3].ObjectivesThe objective was to evaluate the rate of RRA according to three definitions, the agreement between the definitions and major determinants of such definitions in a large monocentric cohort of RA patients.MethodsWe included RA patients treated with any bDMARD (>=1 year), who started bDMARDs after 2001. Considered definitions of RRA were: B-RAA, according to Buch [3], failure of >=1 anti-cytokine (TNF and/or IL6 ihnibitor) and >=1 cell-targeted (B-cell and/or T-cell ihnibitor) bDMARD; KF-RAA, according to Kearsley-Fleet [2], exposed to >=3 bDMARDs classes; DH-RRA, according to de Hair [1], signs and/or symptoms suggestive of inflammatory RA activity (in the study we assumed DAS28>=3.2 or extra-articular manifestations) and failure of >=1 csDMARD and >=2 bDMARDs. Agreement was measured with Cohen’s kappa. To assess variables independently associated with RRA, multivariate regression analysis was used including variables achieving p<0.10 in univariate analysis.ResultsPatients included in the study were 572. B-RRA was observed in 165 (28.8%), KF-RRA in 96 (16.8%) and DH-RRA in 57 (10.0%). DH-RRA was the most stringent definition. Agreement between the definition was fair: DH-RRA and B-RRA kappa=0.330, p<0.001; DH-RRA and KF-RRA kappa=0.260, p<0.001; B-RRA and KF-RRA kappa=0.275, p<0.001. Most common last bDMARD choice in RRA patients differed according to the definition: B-RRA mostly adalimumab (30.9%) (p<0.001), KF-RRA tocilizumab (78.1%) (p<0.001), DH-RRA tocilizumab (33.3%) or abatacept (31.6%) (p<0.001) (Figure). Multivariate analysis revealed that, as expected, all definitions were affected by the number of bDMARDs, and DH-RRA also by the disease activity. Mean PDN daily dose was associated with B-RRA; lower BMI with KF-RRA; the start of bDMARD treatment in earlier years with KF-RRA and DH-RRA; and radiographic progression (in the 24 months before the study) with DH-RRA (Table).ConclusionRRA was observed in a 20-30% of RA patients, slightly higher compared to previous evidence [1,2]. Characteristics of patients fulfilling different RRA definitions are diverse. Particularly, disease severity (disease activity and structural damage) was not associated with RRA if the definition considers only the exposure to bDMARDs. Given the large time span of the study period, RRA patients were more frequently those who started bDMARDs in earlier years.References[1] de Hair MJH, et al. Rheumatology2018;57:1135-1144.[2]. Kearsley-Fleet L, et al. Ann Rheum Dis 2018;77:1405–1412.[3] Buch MH. Ann Rheum Dis 2018;77:966–969. Table. Factors associated with three definitions of difficult-to-treat/refractory rheumatoid arthritis (RRA), multivariate analysis. OR (95% C.I.) p value B-RRA No. bDMARDs 18.77 (11.06;31.85)p<0.001Current bDMARDp<0.001Prednisone daily doseper 5 mg increase2.15 (1.17;2.15)0.014Model Constantp<0.001...
Background::In recent years several biosimilars (BS) of tumour necrosis factor inhibitors (TNF-i) were introduced. At the Padova University Hospital the first BS of etanercept (bsETN) was available in October 2016 and the BS of adalimumab (bsADA) was available in November 2018.Objectives:The objectives of the study were to evaluate the rate of bioriginator-biosimilar (BO-BS) switch in all patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and axial spondiloarthritis (axSpA) in the cohort of the Padova University Hospital and to examine factors favouring BO-BS switch. Secondly, we investigated survival of BO-BS switch and BO treatment and factors associated with longer treatment survival.Methods:We considered all patients on ETN originator (boETN) treatment when the first bsETN was available (1st October 2016) and all patients on ADA originator (boADA) when bsADA was available (1st November 2018). Patients were followed until 30 August 2019 and were classified as BO-BS switchers if they underwent a switch from either boETN or boADA to BS during the follow-up, otherwise they were considered as continuing BO treatment. Factors associated with BO-BS switch were tested with a multivariable regression analysis. To test the survival of the BO-BS switch and of the BO treatment, Cox regression analysis was used including all variables achiving a p<0.10 in univariate analysis tested with Log-rank test and Kaplan-Meier curves.Results:Among 1208 patients (553 RA, 433 PSA, 215 axSpA), 560 (46.3%) patients switched to bsETN (391) or bsADA (169). Mean disease duration was 16 (14.2) years and mean duration of the bDMARD treatment was 96.3 (56.8) months. After adjustment for potential confounders, factors associated with BO-BS switch were a longer disease duration, a shorter duration of previous bDMARD treatments and diagnosis (Tab.1) RA patients had almost a 3 fold increased likelihood of being switched to BS compared to PSA and axSPA, while difference between PSA and axSPA was not significant.Following Cox regression analysis we observed a longer drug survival in BO-BS switchers compared to those continuing with BO (HR 1.38; 95% C.I. 1.2-1.58; p<0.001) (Fig. 1). A longer drug survival was also associated with a longer disease duration (.15years: HR 1.75; 95% C.I. 1.5-2; p<0.001), longer mean duration of previous bDMARDs (.5years: HR 4.1; 95% C.I. 3.5-4.7; p<0.001), and diagnosis (RA vs PSA: HR 1.22; 95% C.I. 1.02-1.47; p=0.030; RA vs axSpA: HR 0.89 95% C.I. 0.067-0.97; p=0.023; PSA vs axSpA: HR 0.66; 95% C.I. 0.57-0.77; p<0.001) (Fig 2).Figure 1.Kaplan-Meier curves for treatment survival, Log-rank test.Figure 2.Kaplan-Meier curves for treatment survival in all patients, Log-rank tesConclusion:BO-BS switch was undertaken in almost half of the patients. Patients with longer disease duration and longer bDMARD duration, were the most likely to be switched successfully to BS. BO-BS switching does not affect the survival of the treatment, indeed, it provides sustained effectiveness particularly if undertaken in patients with stable disease activity.Table 1.Factors associated with BO-BS switch, multivariate regression analysis.Disclosure of Interests:DAVIDE ASTORRI: None declared, Francesca Ometto: None declared, LARA FRISO: None declared, BERND RAFFEINER: None declared, Costantino Botsios: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS
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