The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond ...autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Rheumatoid arthritis (RA) is a highly heterogeneous syndrome in terms of clinical presentation, progression, and response to therapy. In such a complicated context, the identification of ...disease-related biomarkers would be undoubtedly helpful in assisting tailored approaches for every patient. Despite remarkable efforts, however, progress in new biomarker development and validation is dramatically slow. At present, none of the candidate genetic, cellular, or molecular biomarker has yet surpassed the clinical value of RA-specific autoantibodies, including rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA). Rather, recent years have witnessed significant advancements in our understanding of the multiple roles that RF and ACPA play in RA pathophysiology. This has helped clarifying the mechanistic basis of the clinical associations of autoantibodies in RA. In this short review, we will briefly summarize the effector functions of RF and ACPA, and analyse how autoantibodies may help subclassifying RA patients in terms of clinical presentation and response to therapy.
Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension ...of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The management of rheumatoid arthritis has undergone major advances in recent years, both in terms of the drugs armamentarium and therapeutic strategy. Treating disease to target, aiming at ...remission, through a tight control protocol is regarded as the standard of care. Reaching clinical and radiographic disease remission has therefore become an achievable goal. Increasing evidence has demonstrated that early diagnosis, prompt treatment initiation and early achievement of remission are the major predictors of long-term clinical, functional and radiographic outcomes. Concentrating efforts in controlling disease activity in a very early window of opportunity offers unique sustained benefits. In this short review, we analysed the available evidence supporting the value of treating rheumatoid arthritis early and the impact on disease outcomes, with particular focus on radiographic progression.
Prevalence and outcomes of coronavirus disease (COVID)-19 in relation to immunomodulatory medications are still unknown. The aim of the study is to investigate the impact of glucocorticoids and ...immunosuppressive agents on COVID-19 in a large cohort of patients with chronic immune-mediated inflammatory arthritis.
The study was conducted in the arthritis outpatient clinic at two large academic hospitals in the COVID-19 most endemic area of Northern Italy (Lombardy). We circulated a cross-sectional survey exploring the prevalence of severe acute respiratory syndrome-coronavirus-2 nasopharyngeal swab positivity and the occurrence of acute respiratory illness (fever and/or cough and/or dyspnea), administered face-to-face or by phone to consecutive patients from 25 February to 20 April 2020. COVID-19 cases were defined as confirmed or highly suspicious according to the World Health Organization criteria. The impact of medications on COVID-19 development was evaluated.
The study population included 2050 adults with chronic inflammatory arthritis receiving glucocorticoids, conventional-synthetic (cs), or targeted-synthetic/biological (ts/b) disease-modifying drugs (DMARDs). Laboratory-confirmed COVID-19 and highly suspicious infection were recorded in 1.1% and 1.4% of the population, respectively. Treatment with glucocorticoids was independently associated with increased risk of COVID-19 (adjusted OR 95% CI ranging from 1.23 1.04-1.44 to 3.20 1.97-5.18 depending on the definition used). Conversely, patients treated with ts/bDMARDs were at reduced risk (adjusted OR ranging from 0.46 0.18-1.21 to 0.47 0.46-0.48). No independent effects of csDMARDs, age, sex, and comorbidities were observed.
During the COVID-19 outbreak, treatment with immunomodulatory medications appears safe. Conversely, glucocorticoids, even at low-dose, may confer increased risk of infection.
Retrospectively registered. Not applicable.
A proof-of-concept study to evaluate the feasibility and safety of minimally invasive ultrasound (US)-guided synovial biopsy of the radiocarpal (RC) joint using the anatomical snuffbox as an access ...route.
Twenty consecutive patients with active chronic arthritis of the wrist underwent minimally invasive US-guided synovial biopsy of the RC joint using the anatomical snuffbox as the access route. Samples were retrieved from 3 predetermined biopsy target sites of the RC synovia (proximal, vault, and distal site), aiming for a minimum of 12 samples. The procedure's feasibility was evaluated based on the number and histological quality of retrieved tissue fragments tested on pre-defined histometric parameters. The safety and tolerability of the procedure were assessed through 1-week and 1-month follow-up clinical evaluations.
A median number of 17 fragments (≥ 1 mm diameter size at macroscopic evaluation) per procedure was processed for histopathology (range 9-24) and dedicated to the study. At the histopathologic evaluation, a gradable tissue (visible lining layer and ≥ 4 fragments with IST) was recognized in 19/20 biopsies (95%), and all pre-defined histometric parameters were judged applicable and successfully measured in 19/19 gradable biopsies. All three biopsy target sites showed sampling accessibility. The entire procedure was generally well tolerated. At the 1-month follow-up, no patients showed infectious complications.
The access route through the anatomical snuff box in US-guided synovial biopsies of the RC joint allows for a safe and targeted collection of adequate tissue samples. This modification of the traditional access route may allow easier, repeatable, and safer sampling of anatomically distinct areas of the wrist in the course of arthritis.
Background:
Major improvements in the management of rheumatoid arthritis (RA) have made clinical remission an achievable and desirable goal but, despite the relevance gained by a profound disease ...suppression, many patients with RA still miss clinical remission due to several factors influencing disease activity, including treatment adherence.
Objective:
To evaluate the effect of adherence to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on the achievement of clinical remission in a cohort of patients with new-onset inflammatory arthritis.
Study design:
A prospective cohort study was conducted using the ELECTRA database, which consists of clinical data from patients followed at the IRCCS Policlinico San Matteo Foundation (Pavia, Italy), linked to regional administrative healthcare databases.
Methods:
We enrolled patients with new-onset active disease between January 2006 and December 2013 and followed them until their first clinical remission or end of follow-up (December 2015). To assess the association of csDMARD adherence with clinical remission, we estimated the csDMARD proportion of days covered (PDC) during follow-up. PDC was added to the main clinical adjustment covariates as a time-dependent variable in a proportional hazard Cox regression model.
Results:
The cohort included 324 patients with a mean (SD) age of 58 (13.9) and predominantly female (74.5%). A total of 219 patients (67.6%) achieved clinical remission during follow-up and 85 (26.2%) in the first 6 months (early clinical remission). Cox regression models showed that a 10% increment of PDC increased the probability of achieving clinical remission by 10% (p < 0.001) and the probability of early clinical remission by 21% (p = 0.03).
Conclusion:
Patients at disease onset with higher adherence to csDMARDs were more likely to achieve clinical remission and early clinical remission. Our study highlighted the importance of close monitoring of patients to increase their likelihood of following therapeutic indications and achieving favorable disease outcomes, such as lower disability.
Abstract
Background
While low-dose oral glucocorticoids (GCs) are recommended in the management of early arthritis, their impact on mortality is unclear. The aim of this study is to evaluate the ...effect of GCs on mortality in patients with early arthritis, by linking clinical and administrative databases.
Methods
The study included patients with new-onset rheumatoid arthritis (RA) or undifferentiated arthritis (2005–2010), who received DMARDs (MTX in RA or UA with poor prognosis, hydroxychloroquine in UA) and were alive at the second year of follow-up. Low-dose GCs could be prescribed. Clinical and administrative data were linked from Administrative Health Databases (AHD) of the corresponding province, which provided us with information on drug delivery, comorbidities, hospitalization, and mortality. The effect of GCs in the first year was defined using a dichotomous variable or a 3-level categorization (not delivered, ≤7.5 mg/day, or >7.5 mg/day of prednisone) on all-cause mortality, assessed with Cox regression, either crude or adjusted for age, gender, Charlson Comorbidity Index (CCI) or single comorbidities, ACPA, HAQ, and MTX in the first year. A secondary analysis of the effect of GCs on related hospitalizations (for cardiovascular events, diabetes, serious infections, osteoporotic fractures) was also carried.
Results
Four hundred forty-nine patients were enrolled (mean age 58.59, RA 65.03%) of which 51 (11.36%) died during the study. The median (IQR) follow-up was equal to 103.91 (88.03–126.71) months. Treatments with GCs were formally prescribed to 198 patients (44.10%) at ≤7.5 mg/day, although by the end of the study such treatments were received by 257 patients (57.24%); 88 patients (19.6%) were treated with GCs at >7.5 mg/day. In adjusted analyses, the GC delivery (HR, 95% CI 1.35 (0.74, 2.47)) did not significantly predict mortality — both at a low (HR, 95% CI 1.41 (0.73, 2.71)) and at a high (HR, 95% CI 1.23 (0.52, 2.92)) dosage. When “all-cause hospitalization” was used as an outcome, the analysis did not show a difference between patients receiving GC and patients not receiving GC.
Conclusion
In patients with early inflammatory arthritis, the initial GC dose was higher than that prescribed by rheumatologists; however, on background treatment with DMARDs, GC treatments did not seem to increase mortality and hospitalizations.
Background:
The patient global assessment of disease activity (PGA) is the major limiting factor to Boolean remission in patients with established rheumatoid arthritis (RA). Here, we investigated the ...limiting variables to disease remission in patients with early RA treated with conventional synthetic disease modifying anti-rheumatic drugs, also in relation to autoantibody status.
Methods:
Data were retrieved from 535 early RA patients (<12 months of symptoms) with an observation period of 6–12 months upon initiation of therapy with methotrexate aimed at the achievement of low disease activity based on the 28-joints disease activity score. Near-remission was defined as any of the four core items of Boolean remission >1 with the remaining three all ⩽1. Reasons for missing Boolean remission and predictors of near-remission subcategories were analyzed in relation to baseline disease variables.
Results:
After 6 and 12 months, near-remission was two-times more frequent than Boolean remission (25.6% and 26.9% at the two time-points). A 28-swollen joint count (SJC28) >1 was responsible for the majority of near-remission (56.2% and 57.6% at 6 and 12 months, respectively), and PGA > 1 accounted for approximatively 35% of the cases. Autoantibody-positivity independently predicted the risk of missing remission because of SJC28 > 1 adjusted odds ratio (OR) 95% confidence interval (CI) 2.81 (1.59–4.9) at 6 months and 1.73 (1.01–3.01) at 12 months, whilst autoantibody-negativity was an independent predictor of PGA near-remission adjusted OR (95% CI) 2.45 (1.25–4.80) at 6 months and 5.71 (2.47–13.2) at 12 months.
Conclusion:
In early RA, Boolean remission is more frequently missed because of persistent swollen joints. However, barriers to full-remission vary in relation to the autoantibody status. Autoantibody-positive patients more commonly experience residual swollen joints, whilst PGA more frequently impairs remission in autoantibody-negative patients. Efforts to target full-remission in early RA may thus require different strategies according to autoantibody profile.
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