Impact of age and cardiovascular risk factors on the incidence of adverse events in patients with rheumatoid arthritis treated with Janus Kinase inhibitors: data from a real-life multicentric cohort.

Inhibiting Janus Kinases (JAK) is a crucial therapeutic strategy in rheumatoid arthritis (RA). However, the use of JAK inhibitors has recently raised serious safety concerns. The study aims to evaluate the safety profile of JAKi in patients with RA and identify potential risk factors (RFs) for adverse events (AEs). Data of RA patients treated with JAKi in three Italian centers from January 2017 to December 2022 were retrospectively analyzed. 182 subjects (F:117, 64.3%) underwent 193 treatment courses. 78.6% had at least one RF, including age ≥ 65 years, obesity, smoking habit, hypertension, dyslipidemia, hyperuricemia, diabetes, previous VTE or cancer, and severe mobility impairment. We identified 70 AEs (28/100 patients/year), among which 15 were serious (6/100 patients/year). A high disease activity was associated with AEs occurrence (p = 0.03 for CDAI at T0 and T6; p = 0.04 for SDAI at T0 and T6; p = 0.01 and p = 0.04 for DAS28ESR at T6 and T12, respectively). No significant differences in AEs occurrence were observed after stratification by JAKi molecules (p = 0.44), age groups (p = 0.08) nor presence of RFs (p > 0.05 for all of them). Neither the presence of any RFs, nor the cumulative number of RFs shown by the patient, nor age ≥ 65 did predict AEs occurrence. Although limited by the small sample size and the limited number of cardiovascular events, our data do not support the correlation between cardiovascular RFs-including age-and a higher incidence of AEs during JAKi therapy. The role of uncontrolled disease activity in AEs occurrence should by emphasized.

Heterogeneity of determining disease severity, clinical course and outcomes in systemic sclerosis-associated interstitial lung disease: a systematic literature review.

Objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable and different from continuously progressive idiopathic pulmonary fibrosis (IPF). Most proposed definitions of progressive pulmonary fibrosis or SSc-ILD severity are based on the research data from patients with IPF and are not validated for patients with SSc-ILD. Our study aimed to gather the current evidence for severity, progression and outcomes of SSc-ILD.Methods A systematic literature review to search for definitions of severity, progression and outcomes recorded for SSc-ILD was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in Medline, Embase, Web of Science and Cochrane Library up to 1 August 2023.Results A total of 9054 papers were reviewed and 342 were finally included. The most frequent tools used for the definition of SSc-ILD progression and severity were combined changes of carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC), isolated FVC or DLCO changes, high-resolution CT (HRCT) extension and composite algorithms including pulmonary function test, clinical signs and HRCT data. Mortality was the most frequently reported long-term event, both from all causes or ILD related.Conclusions The studies presenting definitions of SSc-ILD 'progression', 'severity' and 'outcome' show a large heterogeneity. These results emphasise the need for developing a standardised, consensus definition of severe SSc-ILD, to link a disease specific definition of progression as a surrogate outcome for clinical trials and clinical practice.PROSPERO registration number CRD42022379254.Cite Now.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Autoimmune Rheumatic and Non Rheumatic Diseases.

The soluble urokinase plasminogen activator receptor (suPAR) is the bioactive form of uPAR, a membrane-bound glycoprotein, and it is primarily expressed on the surface of immunologically active cells. Mirroring local inflammation and immune activation, suPAR has gained interest as a potential prognostic biomarker in several inflammatory diseases. Indeed, in many diseases, including cancer, diabetes, cardiovascular diseases, kidney diseases, and inflammatory disorders, higher suPAR concentrations have been associated with disease severity, disease relapse, and mortality. Our review describes and discusses the supporting literature concerning the promising role of suPAR as a biomarker in different autoimmune rheumatic and non-rheumatic diseases.

Circulating Calprotectin (cCLP) in autoimmune diseases.

BACKGROUND AND AIM: Calprotectin (CLP) is a heterodimeric complex formed by two S100 proteins (S100A8/A9), which plays a pivotal role in innate immunity. Due to its intrinsic cytotoxic and proinflammatory properties, CLP controls cell differentiation, proliferation and NETosis and has been associated with a wide range of rheumatic diseases. Our review summarizes the widespread interest in circulating CLP (cCLP) as a biomarker of neutrophil-related inflammation, in autoimmune rheumatic disease (ARD) and non-ARD. METHODS: A thorough literature review was performed using PubMed and EMBASE databases searching for circulating calprotectin and synonyms S100A8/A9, myeloid-related protein 8/14 (MRP8/MRP14), calgranulin A/B and L1 protein in addition to specific ARDs and autoimmune non-rheumatic diseases. We selected only English-language articles and excluded abstracts without the main text. RESULTS: High cCLP serum levels are associated with worse structural outcomes in rheumatoid arthritis and to a lesser extent, in spondyloarthritis. In addition, cCLP can predict disease relapse in some autoimmune diseases including systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) and some severe manifestations of connective tissue diseases, such as glomerulonephritis in SLE, AAV, juvenile idiopathic arthritis, adult-onset Still's disease and lung fibrosis in systemic sclerosis. Therefore, cCLP levels enable the identification of patients who need an accurate and tight follow-up. The clinical usefulness of cCLP as an inflammatory marker has been suggested for inflammatory/autoimmune non-rheumatic diseases, and especially for the monitoring of the inflammatory bowel diseases patients. Currently, there are only a few studies that evaluated the cCLP efficacy as a clinical biomarker in inflammatory/autoimmune non-rheumatic diseases with controversial results. Future studies are warranted to better clarify the role of cCLP in relation to the disease severity in myasthenia gravis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, Graves' orbitopathy, autoimmune bullous diseases and uveitis. CONCLUSION: Our literature review supports a relevant role of cCLP as potential prognostic biomarker mirroring local or systemic inflammation, especially in chronic inflammatory rheumatic diseases.

JAK inhibitors and autoimmune rheumatic diseases.

The four Janus kinase (JAK) proteins and the seven Signal Transducers of Activated Transcription (STAT) mediate intracellular signal transduction downstream of cytokine receptors, which are involved in the pathology of allergic, autoimmune, and inflammatory diseases. The development of targeted small-molecule treatments with diverse selective inhibitory profiles, such as JAK inhibitors (JAKi), has supported an important change in the treatment of multiple disorders. Indeed, JAKi inhibit intracellular signalling controlled by numerous cytokines implicated in the disease process of rheumatoid arthritis and several other inflammatory and immune diseases. Therefore, JAKi have the capacity to target multiple pathways of those diseases. Other autoimmune diseases treated with JAKi include systemic sclerosis, systemic lupus erythematosus, dermatomyositis, primary Sjogren's syndrome, and vasculitis. In all of these cases, innate immunity stimulation activates adaptive immunity, resulting in the production of autoreactive T cells as well as the stimulation and differentiation of B cells. Mechanism-based treatments that target JAK-STAT pathways have the possibility of improving outcomes by reducing the consumption of glucocorticoids and/or non-specific immunosuppressive drugs in the management of systemic immune-mediated inflammatory diseases.