Neuropsychiatric (NP) involvement is one of the most complex and challenging features of systemic lupus erythematosus (SLE) encompassing the central (CNS), peripheral (PNS) and autonomous nervous ...system (ANS) as defined by the 1999 American College of Rheumatology standard nomenclature and case definitions. NPSLE has a negative impact on patient’s quality of life and is associated with increased morbidity and mortality. The full disease burden of NPSLE is not clearly known, because robust epidemiology studies are lacking or biased by different methodology design. A realistic estimate of the prevalence of NP involvement in SLE is around fifty percent of SLE patients. The challenge of diagnosis: As none of the NP syndromes that occur in SLE have features that are specific for SLE, determination of the correct attribution of NP events in SLE patients is a challenging but critical step in the treatment of individual patients and in performing research studies. In fact, erroneous attribution can lead to suboptimal treatment and to incorrect designation of patient groups in research studies. Approximately 30% of all NP events are attributable to SLE (NPSLE) and present most frequently around the time of SLE onset. Modern and rapidly evolving neuroimaging technologies can help clinicians in both diagnosis and follow up. A multidisciplinary expert team represents the best strategy for NPSLE. The challenge of treatment: The main proposed pathogenetic pathways include both ischemic and neuroinflammatory mechanisms with evidence for complement and microglia activation. Following diagnosis and causal attribution, the treatment of NPSLE should be tailored to the type of NP event, the predominant putative pathogenic mechanism, in addition to the history (acute or chronic), activity and severity of the clinical event. To treat NPSLE, in the absence of high-level evidence, it is necessary to develop pragmatic therapeutic strategies supported by expert opinion, published observational cohort data on NPSLE and extrapolation from experience with other organ system disease in SLE. To date, therapeutic options include symptomatic, anti-thrombotic and immunosuppressive agents. Therapeutic recommendations released by EULAR in 2010 and, more recently, by ACR/EULAR in 2019 are available.1–5 Although neuropsychiatric manifestations of SLE have been recognised for over 100 years, unmet needs for patients with NPSLE still exist, including a lack of diagnostic biomarkers, lack of novel therapies and lack of clinical trials, which should be focused on future research agendas.Learning ObjectivesExplain the diagnostic challenges in NPSLE with focus on the attribution and neuroimagingDiscuss the current knowledge about the main pathogenetic mechanisms of NPSLEExplain the available and novel therapeutic options to treat NPSLEDescribe unmet needs in the approach to the diagnosis and management of NPSLEReferencesGovoni M, Bortoluzzi A, Padovan M, et al. The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J Autoimmun 2016;74:41–72.Bortoluzzi A, Scirè CA, Bombardieri S, et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford) 2015;54(5):891–8.Hanly JG, Kozora E, Beyea SD, et al. Review: Nervous System Disease in Systemic Lupus Erythematosus: Current Status and Future Directions. Arthritis Rheumatol 2019;71(1):33–42.Nikolopoulos D, Fanouriakis A, Boumpas DT. Update on the pathogenesis of central nervous system lupus. Curr Opin Rheumatol 2019;31(6):669–77.Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol 2019;15(3):137–52.
Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by ...the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17-32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.
Rheumatoid arthritis (RA) is a chronic inflammatory disease, affecting mostly women with a female/male ratio of 3:1. It is characterized by symmetrical polyarthritis, leading to progressive joint ...damage. Sex differences have been reported in terms of disease course and characteristics, influencing patients reported outcome measures (PROMs) and pain perception, ultimately leading to male-female disparities in treatment response. Notwithstanding, sex and gender discrepancies are still under-reported in clinical trials. Therefore, there is a consistent need for a precise reference of sex and gender issues in RA studies to improve treat-to-target achievement. This narrative review explores the above-mentioned aspects of RA disease, discussing the latest core principles of RA recommendations, from safety issues to early arthritis concept and management, treat-to-target and difficult-to-treat notions, up to the most recent debate on vaccination. Our final purpose is to evaluate how sex and gender can impact current management guidelines and how this issue can be integrated for effective disease control.
The purpose of this investigation was to characterize Merkel cell carcinomas (MCC) arisen in patients affected by autoimmune diseases and treated with biologic drugs.
Serum samples from patients with ...MCC were analyzed for the presence and titer of antibodies against antigens of the oncogenic Merkel cell polyomavirus (MCPyV). IgG antibodies against the viral oncoproteins large T (LT) and small T (ST) antigens and the viral capsid protein-1 were analyzed by indirect ELISA. Viral antigens were recombinant LT/ST and virus-like particles (VLP), respectively. MCPyV DNA sequences were studied using PCR methods in MCC tissues and in peripheral blood mononuclear cells (PBMC). Immunohistochemical (IHC) analyses were carried out in MCC tissues to reveal MCPyV LT oncoprotein.
MCPyV DNA sequences identified in MCC tissues showed 100% homology with the European MKL-1 strain. PBMCs from patients tested MCPyV-negative. Viral DNA loads in the three MCC tissues were in the 0.1 to 30 copy/cell range. IgG antibodies against LT/ST were detected in patients 1 and 3, whereas patient 2 did not react to the MCPyV LT/ST antigen. Sera from the three patients with MCC contained IgG antibodies against MCPyV VP1. MCC tissues tested MCPyV LT-antigen-positive in IHC assays, with strong LT expression with diffuse nuclear localization. Normal tissues tested MCPyV LT-negative when employed as control.
We investigated three new MCCs in patients affected by rheumatologic diseases treated with biologic drugs, including TNF. A possible cause-effect relationship between pharmacologic immunosuppressive treatment and MCC onset is suggested. Indeed, MCC is associated with MCPyV LT oncoprotein activity.
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Background
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by necrotizing inflammation of small- and medium-sized blood vessels and the ...presence of circulating ANCA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic ANCA-associated vasculitis, characterized by peripheral eosinophilia, neuropathy, palpable purpuras or petechiae, renal and cardiac involvement, sinusitis, asthma, and transient pulmonary infiltrates. Middle lobe syndrome (MLS) is defined as recurrent or chronic atelectasis of the right middle lobe of the lung, and it is a potential complication of asthma.
Case presentation
Herein, we describe a case of MLS in a 51-year-old woman, never-smoker, affected by EGPA, presenting exclusively with leukocytosis and elevated concentrations of acute-phase proteins, without any respiratory symptom, cough, or hemoptysis. Chest computed tomography (CT) imaging documented complete atelectasis of the middle lobe, together with complete obstruction of lobar bronchial branch origin. Fiberoptic bronchoscopy (FOB) revealed complete stenosis of the middle lobar bronchus origin, thus confirming the diagnosis of MLS, along with distal left main bronchus stenosis. Bronchoalveolar lavage (BAL) did not detect any infection. Bronchial biopsies included plasma cells, neutrophil infiltrates, only isolated eosinophils, and no granulomas, providing the hypothesis of vasculitic acute involvement less likely. First-line agents directed towards optimizing pulmonary function (mucolytics, bronchodilators, and antibiotic course) were therefore employed. However, the patient did not respond to conservative treatment; hence, endoscopic management of airway obstruction was performed, with chest CT documenting resolution of middle lobe atelectasis.
Conclusion
To the best of our knowledge, this is the first detailed description of MLS in EGPA completely resolved through FOB. Identification of MLS in EGPA appears essential as prognosis, longitudinal management, and treatment options may differ from other pulmonary involvement in AAV patients.
The aim of this study was to develop and validate an algorithm to assist the attribution of neuropsychiatric (NP) events to underlying disease in SLE patients.
Phase 1 identified and categorized ...candidate items to be included in the algorithm for the attribution of an NP event to SLE and their relative weights through a literature-informed consensus-driven process. Using a retrospective training cohort of SLE, phase 2 validated items selected in phase 1 and refined weights through a data-driven process, fitting items as independent variables and expert evaluation (clinical judgement) as reference standard in logistic models. Phase 3 consisted of a validation process using an external multicentre retrospective SLE cohort.
Phase 1 identified four different items: timing of the NP event, type of event, confounding factors and favouring factors. The training and validating cohorts included 228 and 221 patients, respectively. Each patient experienced at least one NP event characterized using the ACR case definition. In these samples, items selected in phase 1 showed good performance in discriminating patients with NPSLE: the area under the receiver operating characteristic curve using dichotomous outcomes was 0.87 in the training set and 0.82 in the validating set. Relevant cut-offs of the validated score identify events with a positive predictive value of 100% (95% CI 93.2, 100) and 86.3% (95% CI 76.2, 93.2) in the training and validating cohorts, respectively.
A new algorithm based on a probability score was developed and validated to determine the relationship between NP events and SLE.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes ...disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the
gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (
= 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (
= 0.032). Our preliminary results showed that the genetic polymorphisms in the
gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.
Abstract
Objective
To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients.
Methods
The Early Lupus Project recruited an inception cohort ...of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors independently associated with the risk of damage development.
Results
Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6, older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage.
Conclusion
We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.
Inflammatory arthritis (IAs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are characterized by the presence of chronic synovitis. The Krenn's synovitis score (KSS), a simple tool ...detectable by haematoxylin/eosin staining of synovial biopsy samples, allows the discrimination between high-grade and low-grade synovitis. The aim of this study was to identify the clinical associations of KSS and to evaluate the relationship between high-grade synovitis and treatment response in IA patients.
Clinical, laboratory and ultrasound data were retrieved from RA and PsA patients recruited in the prospective MATRIX cohort study. Inclusion criteria were age≥18 years, RA or PsA diagnosis, and presence of active disease with eligibility to start/modify therapy. Patients underwent ultrasound-guided synovial biopsy of one of the most involved joints before starting/modifying treatment according to treat-to-target strategy. The samples were analysed by an expert pathologist for KSS calculation. Univariable and multivariable logistic regression analyses were performed to evaluate the relationship between KSS and baseline variables. The association between KSS and treatment response at 24 weeks of follow-up was investigated in univariable logistic regression analysis.
53 patients, 34 RA and 19 PsA, completed 24 weeks of follow-up after synovial biopsy. Patients were either treatment naïve (N=6, 11%), csDMARDs-experienced (N=46, 87%) or b/tsDMARDs-experienced (N=20, 38%). Median KSS was 6.00 (Q1-Q3 4.00-7.00) in RA and 4.00 (3.00-6.00) in PsA (p=0.040), and inflammatory infiltrates score was significantly higher in RA than in PsA patients (median 3.00 vs 2.00, p=0.021). In multivariable analysis, synovial effusion in the biopsied joint (OR 9.26, 95%CI 2.12-53.91) and erythrocyte sedimentation rate (ESR) (OR 1.04, 95%CI 1.01-1.08) associated with high KSS. High-grade synovitis significantly associated with a higher probability of achieving DAS28 remission, ACR20/50 response, and Boolean2.0 remission, independently from diagnosis.
Several markers of pro-inflammatory pathways associated with the presence of high-grade synovitis, and patients with higher KSS shared a higher probability of treatment targets achievement in the follow up. The integration of a simple and feasible tool like KSS in the clinical and prognostic stratification of patients with IA might help in intercepting patients with a disease more prone to respond to available treatment paradigms.
This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet's syndrome ...(BS) over 2 years of follow-up.
Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains.
During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) (p <0.001). The incidence rate of damage accrual was stable over time, regardless of the disease duration. Out of 61 new BODI items, 25 (41.0%) were considered related to glucocorticoid (GC) use. In multivariate analysis, duration of GC therapy (OR per 1-year 1.15, 95% CI 1.07-1.23; p <0.001) and occurrence of ≥1 disease relapse (OR 3.15, 95% CI 1.09-9.12; p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08-0.54, p<0.001). Damage accrual was independently associated with the impairment of different physical domains and, to a greater extent, in emotional domains of the SF-36 questionnaire. Female sex, higher disease activity, and fibromyalgia were also significantly associated with impairment in HR-QoL.
In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.
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