Real-Life Comparison of Four JAK Inhibitors in Rheumatoid Arthritis (ELECTRA-i Study).

Background: Real-world evidence of the efficacy and adverse events of JAK inhibitor treatment (Tofacitinib, Baricitinib, Upadacitinib, and Filgotinib) in rheumatoid arthritis is still limited. Methods: We studied 115 patients from the Rheumatology Unit of S. Giovanni di Dio Hospital affected by D2T-RA, according to the 2010 EULAR criteria. Out of the 115 patients, 17 had been treated with Baricitinib 8 mg/daily, 32 with Filgotinib 200 mg/daily, 21 with Tofacitinib 10 mg/daily, and 45 with Upadacitinib 15 mg/daily. We evaluated the clinical response after 3, 6, and 12 months of treatment and the follow-up from September 2022 to September 2023. All patients were evaluated according to the number of tender joints (NTJs), number of swollen joints (NSJs), visual analog scale (VAS), global assessment (GA), health assessment questionnaire (HAQ), Disease Activity Score (DAS28), and CDAI. Furthermore, laboratory parameters of efficacy and tolerability were evaluated. Results: All treatments demonstrated a statistically significant decrease in the DAS28 and CDAI scores, tender and swollen joint counts, VAS, HAQ, and patient global assessment (PGA) after 3, 6, and 12 months of treatment. All treatments showed similar behavior, and statistically significant decreases in circulating calprotectin, TNFα, and IL-6 were observed for all drugs after 12 months of treatment. In addition, soluble urokinase plasminogen activator receptor (suPAR) values showed significant differences at baseline and after 12 months of treatment for Filgotinib: 4.87 ± 4.53 vs. 3.61 ± 0.9 (0.009) and Upadacitinib: 6.64 ± 7.12 vs. 4.06 ± 3.61 (0.0003), while no statistically significant differences were found for Baricitinib: 3.4 ± 0.1 vs. 3.78 ± 0.1 and Tofacitinib: 3.95 ± 1.77 vs. 2.58 ± 0.1. The TC/HDL-C ratio (atherogenic index) showed significant differences when comparing Baricitinib vs. Filgotinib (0.0012), Filgotinib vs. Tofacitinib (0.0095), and Filgotinib vs. Upadacitinib (0.0001); furthermore, the LDL-C/HDL-C ratio in the Filgotinib group did not change (2.37 ± 0.45 vs. 2.35 ± 2.13 (NS)) after 12 months of treatment. Venous Thrombotic Events (VTEs) and major adverse cardiovascular events (MACEs) accounted for 1% of adverse events after treatment with Baricitinib. Herpes zoster reactivation accounted for 1% of adverse events after treatment with Filgotinib and Tofacitinib, while non-melanoma skin cancer (NMSC) accounted for 1% of adverse events after Upadacitinib treatment. Conclusions: Our real-world data from patients with RA show differences in some laboratory parameters and in the impact of lipid metabolism in JAK inhibitor treatment.

Older Age, a High Titre of Neutralising Antibodies and Therapy with Conventional DMARDs Are Associated with Protection from Breakthrough Infection in Rheumatoid Arthritis Patients after the Booster Dose of Anti-SARS-CoV-2 Vaccine.

Objectives: We aimed to analyse the incidence and severity of breakthrough infections (BIs) in rheumatoid arthritis (RA) patients after a COronaVIrus Disease 2019 (COVID-19) vaccination booster dose. Methods: We enrolled 194 RA patients and 1002 healthcare workers (HCWs) as controls. Clinical, lifestyle and demographic factors were collected at the time of the third dose, and immunogenicity analyses were carried out in a subgroup of patients at 4-6 weeks after the third dose. Results: BIs were experienced by 42% patients (82/194) with a median time since the last vaccination of 176 days. Older age (>50 years; aHR 0.38, 95% CI: 0.20-0.74), receiving conventional synthetic disease modifying antirheumatic drugs (csDMARDs) (aHR 0.52, 95%CI: 0.30-0.90) and having a titre of neutralising antibodies >20 (aHR 0.36, 95% CI: 0.12-1.07) were identified as protective factors. Conversely, anti-IL6R treatment and anti-CD20 therapy increased BI probability. BIs were mostly pauci-symptomatic, but the hospitalisation incidence was significantly higher than in HCWs (8.5% vs. 0.19%); the main risk factor was anti-CD20 therapy. Conclusions: Being older than 50 years and receiving csDMARDs were shown to be protective factors for BI, whereas anti-IL6R or anti-CD20 therapy increased the risk. Higher neutralising antibody titres were associated with a lower probability of BI. If confirmed in a larger population, the identification of a protective cut-off would allow a personalised risk-benefit therapeutic management of RA patients.

ReLiFiRa (Real Life Filgotinib in Rheumatoid Arthritis): Retrospective Study of Efficacy and Safety in Common Clinical Practice.

BACKGROUND: Filgotinib (FIL) is a selective JAK1 inhibitor with an affinity 30-fold higher than JAK2, approved to treat moderate to severe active rheumatoid arthritis (RA), in adults with inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). METHODS: We conducted a retrospective, multicentric study in order to evaluate efficacy and safety of FIL 200 mg daily therapy, after 3 and 6 months, in 120 patients affected by RA, managed in Tuscany and Umbria rheumatological centers. The following clinical records were analyzed: demographical data, smoking status, previous presence of comorbidities (Herpes zoster -HZ- infection, venous thromboembolism -VTE-, major adverse cardiovascular events -MACE-, cancer, diabetes, and hypertension), disease duration, presence of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), number of biological failures, and prior csDMARDs utilized. At baseline, and after 3 (T3) and 6 (T6) months of FIL therapy, we evaluated mean steroid dosage, csDMARDs intake, clinimetric indexes (DAS28, CDAI, HAQ, patient and doctor PGA, VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and body mass index (BMI). RESULTS: At baseline, the mean disease duration was 9.4 ± 7.5 years; the prevalence of previous HZ infection, VTE, MACE, and cancer was respectively 4.12%, 0%, 7.21%, and 0.83%, respectively. In total, 76.3% of patients failed one or more biologics (one biological failure, 20.6%; two biological failures, 27.8%; three biological failures, 16.5%; four biological failures, 10.3%; five biological failures, 1.1%). After 3 months of FIL therapy, all clinimetric index results significantly improved from baseline, as well as after 6 months. Also, ESR and CRP significatively decreased at T3 and T6. Two cases of HZ were recorded, while no new MACE, VTE, or cancer were recorded during the observation time. CONCLUSION: Despite the limitations of the retrospective study and of the observational period of only 6 months, real-life data on the treatment of RA patients with FIL demonstrate that this Jak inhibitor therapy is safe in terms of CV, VTE events, and occurrence of cancer, and is also effective in a population identified as "difficult to treat" due to failure of previous b-DMARD therapy.

A patient-driven registry on Behçet's disease: the AIDA for patients pilot project.

Introduction: This paper describes the creation and preliminary results of a patient-driven registry for the collection of patient-reported outcomes (PROs) and patient-reported experiences (PREs) in Behçet's disease (BD). Methods: The project was coordinated by the University of Siena and the Italian patient advocacy organization SIMBA (Associazione Italiana Sindrome e Malattia di Behçet), in the context of the AIDA (AutoInflammatory Diseases Alliance) Network programme. Quality of life, fatigue, socioeconomic impact of the disease and therapeutic adherence were selected as core domains to include in the registry. Results: Respondents were reached via SIMBA communication channels in 167 cases (83.5%) and the AIDA Network affiliated clinical centers in 33 cases (16.5%). The median value of the Behçet's Disease Quality of Life (BDQoL) score was 14 (IQR 11, range 0-30), indicating a medium quality of life, and the median Global Fatigue Index (GFI) was 38.7 (IQR 10.9, range 1-50), expressing a significant level of fatigue. The mean Beliefs about Medicines Questionnaire (BMQ) necessity-concern differential was 0.9 ± 1.1 (range - 1.8-4), showing that the registry participants prioritized necessity belief over concerns to a limited extent. As for the socioeconomic impact of BD, in 104 out of 187 cases (55.6%), patients had to pay from their own pocket for medical exams required to reach the diagnosis. The low family socioeconomic status (p < 0.001), the presence of any major organ involvement (p < 0.031), the presence of gastro-intestinal (p < 0.001), neurological (p = 0.012) and musculoskeletal (p = 0.022) symptoms, recurrent fever (p = 0.002), and headache (p < 0.001) were associated to a higher number of accesses to the healthcare system. Multiple linear regression showed that the BDQoL score could significantly predict the global socioeconomic impact of BD (F = 14.519, OR 1.162 [CI 0.557-1.766], p < 0.001). Discussion: Preliminary results from the AIDA for Patients BD registry were consistent with data available in the literature, confirming that PROs and PREs could be easily provided by the patient remotely to integrate physician-driven registries with complementary and reliable information.

The Third Dose of BNT162b2 COVID-19 Vaccine Does Not "Boost" Disease Flares and Adverse Events in Patients with Rheumatoid Arthritis.

Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine in a cohort of rheumatoid arthritis (RA) patients followed-up from the first vaccine cycle to the third dose. The vaccine showed an overall good safety profile with no patient reporting serious AEs, and a low percentage of total AEs at both doses (40/78 (51.3%) and 13/47 (27.7%) patients after the second and third dose, respectively (p < 0.002). Flares were observed in 10.3% of patients after the end of the vaccination cycle and 12.8% after the third dose. Being vaccinated for influenza was inversely associated with the onset of AEs after the second dose, at both univariable (p = 0.013) and multivariable analysis (p = 0.027). This result could allow identification of a predictive factor of vaccine tolerance, if confirmed in larger patient populations. A higher disease activity at baseline was not associated with a higher incidence of AEs or disease flares. Effectiveness was excellent after the second dose, with only 1/78 (1.3%) mild breakthrough infection (BI) and worsened after the third dose, with 9/47 (19.2%) BI (p < 0.002), as a probable expression of the higher capacity of the Omicron variants to escape vaccine recognition.

Correction: Benucci et al. Predicting Loss of Efficacy after Non-Medical Switching: Correlation between Circulating TNF-α Levels and SB4 in Etanercept to SB4 Switchers and Naïve Patients with Rheumatic Disease. J. Pers. Med. 2022, 12, 1174.

The authors wish to make the following correction to this paper [...].

The Association of uPA, uPAR, and suPAR System with Inflammation and Joint Damage in Rheumatoid Arthritis: suPAR as a Biomarker in the Light of a Personalized Medicine Perspective.

BACKGROUND: In recent years, the involvement of the soluble urokinase Plasminogen Activator Receptor (suPAR) in the pathophysiological modulation of Rheumatoid Arthritis (RA) has been documented, resulting in the activation of several intracellular inflammatory pathways. METHODS: We investigated the correlation of urokinase Plasminogen Activator (uPA)/urokinase Plasminogen Activator Receptor (uPAR) expression and suPAR with inflammation and joint damage in RA, evaluating their potential role in a precision medicine context. RESULTS: Currently, suPAR has been shown to be a potential biomarker for the monitoring of Systemic Chronic Inflammation (SCI) and COVID-19. However, the effects due to suPAR interaction in immune cells are also involved in both RA onset and progression. To date, the literature data on suPAR in RA endorse its potential application as a biomarker of inflammation and subsequent joint damage. CONCLUSION: Available evidence about suPAR utility in the RA field is promising, and future research should further investigate its use in clinical practice, resulting in a big step forward for precision medicine. As it is elevated in different types of inflammation, suPAR could potentially work as an adjunctive tool for the screening of RA patients. In addition, a suPAR system has been shown to be involved in RA pathogenesis, so new data about the therapeutic response to Jak inhibitors can represent a possible way to develop further studies.

Predicting Loss of Efficacy after Non-Medical Switching: Correlation between Circulating TNF-α Levels and SB4 in Etanercept to SB4 Switchers and Naïve Patients with Rheumatic Disease.

BACKGROUND: We investigated how the non-medical switching (NMS) between Etanercept (ETN)/originator and SB4/biosimilar affects treatment efficacy in a rheumatic disease (RD) cohort, evaluating some laboratory parameters as loss of efficacy predictors after NMS. METHODS: We enrolled 124 patients with RD (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis): 79 switchers from ETN/originator to SB4 and 45 naïve patients receiving SB4 (first biological treatment). At baseline, 6 (T1), and 12 months (T2), clinical and laboratory parameters were evaluated. RESULTS: In naïve patients, TNF-α significantly increased at T1 in responders (NR) and non-responders (NNR). TNF-α was lower in NNR than in NR at T1 and T2. In NR and NNR, drug levels (DL) increased between T1 and T2. However, DLs were lower in NNR than in NR at T1 and T2.&nbsp;TNF-α was higher in switcher responders (SR) than in non-responders (SNR) at T1 and T2. In SNR, DLs were higher at baseline than in SR, but they decreased significantly at T1 and T2. CONCLUSIONS: We observed a decrease in DL and TNF-α levels after NMS in SNR. Moreover, in naïve patients, DL and TNF-α levels were higher in NR than in NNR. Monitoring DL and TNF-α levels may represent a future precision medicine approach to predict loss of efficacy after NMS.

Development and implementation of the AIDA International Registry for patients with Behçet's disease.

Purpose of the present paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients with Behçet's disease (BD). The Registry is a clinical physician-driven non-population- and electronic-based instrument implemented for the retrospective and prospective collection of real-life data about demographics, clinical, therapeutic, laboratory, instrumental and socioeconomic information from BD patients; the Registry is based on the Research Electronic Data Capture (REDCap) tool, which is thought to collect standardised information for clinical real-life research, and has been realised to change over time according to future scientific acquisitions and potentially communicate with other existing and future Registries dedicated to BD. Starting from January 31st, 2021, to February 7th, 2022, 110 centres from 23 countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 5993 fields organised into 16 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. The development of the AIDA International Registry for BD patients will facilitate the collection of standardised data leading to real-world evidence, enabling international multicentre collaborative research through data sharing, international consultation, dissemination of knowledge, inclusion of patients and families, and ultimately optimisation of scientific efforts and implementation of standardised care.Trial registration NCT05200715 in 21/01/2022.

Vaccination for SARS-CoV-2 in Patients With Psoriatic Arthritis: Can Therapy Affect the Immunological Response?

Background: A few studies on vaccination in patients with rheumatic diseases, including arthritis, connective tissue diseases, vasculitis, and psoriatic arthropathy (PsA), demonstrated reduced production of neutralizing antibodies to SARS-CoV-2 Spike RBD (receptor-binding domain contained in the N-terminal of the S1 globular head region) when compared to the general population. Objective: The aim of our study was to observe whether different therapies for PsA [methotrexate, anti-TNF antibodies, soluble TNF receptor (etanercept) or IL-17 inhibitors] have a different impact on SARS-CoV-2 vaccination in a homogeneous population of patients. Methods: We enrolled 110 PsA patients in remission, assessed with Disease Activity in PSoriatic Arthritis (DAPSA). Of these: 63 were in treatment with anti-TNF-α therapy (26 etanercept, 15 certolizumab, 5 golimumab, 17 adalimumab); 37 with anti-IL17 secukinumab; 10 with methotrexate. All patients underwent vaccination for SARS-CoV-2 with mRNA BNT162b2 vaccine. Assessment of absolute and percentage lymphocyte subsets and anti-SARS-CoV-2 Spike RBD IgG antibody value 3 weeks after the second vaccine dose were performed. In addition, the serum antibody levels of 96 healthy healthcare workers (HCW) were analyzed. Results: The mean disease activity assessed with DAPSA score was 2.96 (SD = 0.60) with no significant differences between patients under different medications (p = 0.779). Median levels of neutralizing antibodies to SARS-CoV-2 Spike RBD were 928.00 binding antibody unit (BAU)/mL [IQR 329.25, 1632.0]; 1068.00 BAU/ml [IQR 475.00, 1632.00] in patients taking MTX, 846.00 BAU/ml [IQR 125.00, 1632.00] in patients taking etanercept, 908.00 BAU/mL [IQR 396.00, 1632.00] in patients taking anti-IL17 and 1148.00 BAU/ml [IQR 327.00, 1632.00] in patients taking TNF-α inhibitors, without statistically significant differences between these groups. Mean serum antibody level of HCW group was 1562.00 BAU/ml [IQR 975.00, 1632.00], being significantly higher than in the patient group (p = 0.000816). Absolute and percentage count of lymphocyte subsets were not statistically different between the subgroups under different treatments and when compared with HCW. Conclusions: As for other rheumatic diseases on immunomodulatory treatment, our data showed a reduced humoral response in PsA patients compared to the control group. However, antibody response did not significantly differ between groups treated with different medications.

Do new and old biomarkers of early undifferentiated arthritis correlate with Arthritis Impact Measurement Scales?

OBJECTIVES: In early undifferentiated arthritis (EUA), the relationship between inflammatory biomarkers and disability is still unclear. The aim of this study was to correlate inflammatory biomarkers with the Arthritis Impact Measurement Scales (AIMS) in EUA. METHODS: Seventy patients with EUA were compared with 20 patients with established rheumatoid arthritis (RA). The association of AIMS [mobility, physical impairment (PI), dexterity, household activities, activities of daily living (ADL), social activity, pain, anxiety, depression] with serum laboratory [phase acute reactants, calprotectin, interleukin-6, tumour necrosis factor (TNF)-α, rheumatoid factor, anti-nuclear and anti-citrullinated peptide antibodies, HLA-DRB], clinical [Clinical Disease Activity Index (CDAI), fatigue, pain and stiffness NRS], x-ray and ultrasound biomarkers was analysed with non-parametric Spearman's rank correlation and Mann-Whitney U tests. RESULTS: No differences in AIMS were found between EUA and established RA patients, or between EUA patients that evolved into early RA (n=17) and those that remained EUA (n=53) at six months of follow-up. In EUA, erythrocyte sedimentation rate correlated with mobility impairment, PI and depression (p=0.04, p=0.03 and p=0.022, respectively), TNF-α correlated with PI (p=0.01) and calprotectin with anxiety (p=0.02). HLA-DRB1*11-positive EUA patients had lower ADL deficiency (p=0.006), depression (p=0.0004) and anxiety (p=0.01). CDAI correlated with PI (p=0.01) and pain (p=0.01), fatigue with PI (p=0.0001) and ADL (p=0.009), stiffness with PI (p=0.01), and Power Doppler ultrasound synovitis with PI (p=0.02) and pain (p=0.007). CONCLUSIONS: In EUA, physical and mood disorders are associated with new and old inflammatory serological, clinical and imaging biomarkers. HLA-DRB1*11-positivity may be protective against these disease-related features.

Therapeutic Potential of Ixekizumab in the Treatment of Ankylosing Spondylitis: A Review on the Emerging Clinical Data.

Over the last 20 years, the greatly improved knowledges of underlying pathogenic mechanisms of AS, including the role of tumor necrosis factor (TNF), the interleukin 23/Th17 axis, and interleukin-17 (Il-17), constituted the rationale to develop biologics selectively inhibiting these pathways. For more than 10 years, anti-TNF biologics were successfully employed to treat AS, with marked improvement of signs and symptoms in around 60% of the patients. Recent knowledge of the pathophysiology of spondyloarthritis has highlighted the emerging role of the IL-17/IL-23 axis. New therapies with selective biological drugs have emerged in the treatment of this pathology. In this review, we evaluated the effects of ixekizumab, a new anti-IL-17A, that was licensed both by EMA and FDA in August 2019 for the treatment of ankylosing spondylitis. The review highlights the efficacy and safety data of the 3 randomized controlled trials (COAST V-COAST W-COAST X) and those of the extension to 52 weeks of COAST V and COAST W.

The Laboratory Role in anti-TNF Biological Therapy Era.

Along years, the advent of biological therapy widely modified treatment of rheumatic diseases and other disorders. However, many agents may elicit in anti-drug antibodies (ADAbs) upon consecutive infusions, with a loss of response. For the right strategy of a personalized medicine, the therapeutic monitoring of TNF-α inhibitors and ADAbs represents an important effort in diagnostic-therapeutic pathway, to improve overall patient management and favoring an appropriate clinical approach. A raising number of diagnostic tests have been designed to elucidate the efficacy and/or safety of a specific drug or class of drugs for a targeted patient's group. Our paper reviewed the current understanding of the immunogenicity of biological drugs employed in the treatment of inflammatory diseases underlying the laboratory role.

Two Novel Technologies for the Detection of Anti-cardiolipin and Anti ß2-Glycoprotein Antibodies in the Real Life: Chemiluminescent in Comparison to the Addressable Laser Bead Immunoassays.

In the present study, we evaluated two novel technologies, the chemiluminescent immunoassay (CIA) QUANTA Flash on BIO-FLASH (Inova Diagnostics, San Diego, CA, USA) and the addressable laser bead immunoassay (ALBIA) on BioPlex™ 2200 (Bio-Rad, Hercules, CA, USA) for the detection of anti-cardiolipin IgG/IgM (aCL) and anti-ß2-glycoprotein IgG/IgM (aß2GPI) antibodies. The study was performed on 134 samples from consecutive patients (59 males and 75 females, mean age 54 ± 10 years) who consulted a rheumatologist because thrombosis and/or pregnancy complications were present or another immunological disease (Sjogren's syndrome, inflammatory arthritis). Fourteen patients of the total fulfilled 25the Sydney criteria for APS and for these patients previous results of aPLs were available. Sera were tested for aCL and aß2GPI of IgG and IgM isotypes using CIA (BIO-FLASH) and ALBIA (BioPlex™ 2200). Overall agreement between CIA and ALBIA ranged from 88.1% (aCL IgG) to 97.8% (aß2GPI IgG). Cohen's kappa coefficient ranged from 0.53 to 0.91, implying moderate to almost perfect agreement. Almost perfect agreement was found between BioPlex™ 2200 and BIO-FLASH aß2GPI IgG and aCL IgM with Cohen's kappa of 0.91 and 0.88, respectively. On the other hand, moderate agreement was found between BioPlex™ 2200 and BIO-FLASH aCL IgG and ß2GPI IgM assays with Cohen's kappa of 0.57 and 0.53, respectively. The two novel technologies look promising and comparable but further studies with larger cohorts are needed to contribute to the better understanding of the new aPLs antibodies assays performance.