Identification of autoantibodies against PsoP27 in synovial fluid derived from psoriatic arthritis and rheumatoid arthritis patients.

PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA (n = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA (n = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients (n = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) (p < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.

Ex-vivo Cell-based Assay for Assessment of Response to TNF Inhibitors in Patients with Rheumatic Diseases.

OBJECTIVE: TNF inhibitors (TNFi) comprise 5 products whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of the patients respond inadequately to TNFi. The different TNFi downstream signalling may lead to their clinical efficacy. Several reports showed that TNFi exhibited differential effects on Th17 cells. We analyzed the different TNFi effects on IL-17A expression in the peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases in order to evaluate the predictive capability of responses in an ex-vivo setting. METHODS: PBMCs were co-cultured with the different TNFi or medium (control), and IL-17A mRNA levels were analyzed by qPCR. IL-17A expression levels in response to 4 TNFi (except certolizumab pegol) were compared with control. IL-17A expression in the assay was correlated to the clinical responses. Assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. RESULTS: The results of a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the different TNFi with 89.5% accuracy. The assay predicted the responses of a prospective cohort (n = 54) to specific TNFi with 79% accuracy. CONCLUSION: This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.

Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Overview of Therapies and a Personalized Approach to Optimized Combined Therapy.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 (PD-L1) antibodies, are currently widely used in oncology clinical practice, achieving considerable success in improving disease outcomes. New checkpoint targets are being discovered and investigated through basic science research and clinical trials. ICI remove negative regulatory immune signals on T cells, leading to immune activation and induction of antitumor immunity. Patients who receive ICI, however, are at risk for developing immune-related adverse events (irAEs), which are attributed to increased T cell activity against antigens in both tumors and in healthy tissues, to increased inflammatory cytokine levels, to increased levels of preexisting autoantibodies, and to enhanced complement-mediated inflammation. Arthritis is one of the most common irAEs. ICI-induced rheumatic irAEs are categorized by levels of severity which guide the choice of treatment options. Management of ICI-induced rheumatic irAEs includes the use of glucocorticoids, disease-modifying antirheumatic drugs (mainly methotrexate), and biological agents (e.g., tumor necrosis factor, interleukin-6 receptor, and CD20 inhibitors). This review aims to summarize the current ICI subtypes, their role in rheumatic irAEs development, and therapies currently used in clinical practice to manage irAEs. In addition, we propose to use an ex vivo personalized diagnostic assay for the selection of the most effective ICI with antirheumatic drugs combinations that will inhibit the advancement of ICI-induced adverse events.

The association between sonographic enthesitis with sonographic synovitis and tenosynovitis in psoriatic arthritis patients.

OBJECTIVES: To examine the association between sonographic enthesitis with sonographic synovitis and tenosynovitis in PsA patients, and the association between sonographic enthesitis and clinical characteristics. METHODS: Consecutive PsA patients that fulfilled the ClASsification criteria for Psoriatic ARthritis (CASPAR) were prospectively recruited. Each patient was evaluated by comprehensive clinical and sonographic assessment (greyscale and Doppler), the latter including 52 joints, 40 tendons and 14 entheses [according to MAdrid Sonography Enthesitis Index (MASEI) plus lateral epicondyles] performed by an experienced sonographer blinded to the clinical data. The US enthesitis score was further categorized to inflammatory (hypoechogenicity, thickening, bursitis and Doppler) and structural (enthesophytes/calcifications and erosions) subcategories. Multivariate linear regression models assessed the association between enthesitis and the selected variables. RESULTS: A total of 158 PsA patients [mean (s.d.) age 52.3 (13) years, 88 (55.7%) females] were analysed. Multivariate linear regression analyses showed a significant association between sonographic enthesitis and sonographic synovitis (ß = 0.18, P = 0.008) and between sonographic enthesitis and sonographic tenosynovitis (ß = 0.06, P = 0.02). These associations were derived from the enthesitis inflammatory subcategory of the MASEI (P < 0.05). Associations between enthesitis and synovitis were also demonstrated on the level of the elbow, knee and ankle joints (P < 0.05). In addition, sonographic enthesitis was significantly associated with older age, male sex, swollen joint count, CRP level and physical occupation. CONCLUSIONS: Sonographic enthesitis is associated with sonographic synovitis and tenosynovitis. The severity of sonographic enthesitis may represent a marker for inflammatory activity in other musculoskeletal domains.

Effect of Secukinumab and Tumor Necrosis Factor Inhibitors on Humoral Response to BNT162b2 mRNA Vaccine in Patients With Spondyloarthritis Compared to Immunocompetent Controls.

OBJECTIVE: To assess the humoral response to the BNT162b2 mRNA vaccine among patients with spondyloarthritis (SpA) receiving secukinumab (SEC) compared to those receiving tumor necrosis factor inhibitors (TNFi) and immunocompetent controls. METHODS: Consecutive patients with psoriatic arthritis or axial SpA receiving SEC (n = 37) or TNFi (monotherapy, n = 109; + methotrexate [MTX], n = 16), immunocompetent controls (n = 122), and patients with rheumatoid arthritis (RA) receiving TNFi therapy (controls, n = 50) were vaccinated with 2 or 3 doses of the BNT162b2 vaccine. We evaluated humoral response, adverse events, and disease activity, and monitored for breakthrough coronavirus disease 2019 (COVID-19) postvaccination. RESULTS: The 2-dose vaccine regimen induced a comparable seropositive response in all study groups. S1/S2 antibody titers (in binding antibody units/mL; mean [SD]) were higher in the SEC group vs the TNFi + MTX-SpA and TNFi-RA groups (192.5 [68.4] vs 104.6 [46.9], P < 0.001, and 143.1 [81.9], P = 0.004). After 6 months, 96.3%, 96.6%, and 80.9% of the SEC, immunocompetent, and TNFi monotherapy-SpA groups (P = 0.10), respectively; 66.7% of the TNFi + MTX-SpA group (P = 0.03); and 63% of the TNFi-RA group (P = 0.004) remained seropositive. S1/S2 antibody titer decline was steeper in the TNFi groups than the SEC group. After the third dose, 100% of the SpA and immunocompetent and 88.9% of the TNFi-RA (P = 0.25) groups were seropositive. Rate of breakthrough COVID-19 infection was higher in the TNFi groups than in the SEC group (36-37.5% vs 10.8%). No significant between-group differences were observed for postvaccination disease activity and adverse events. CONCLUSION: SEC did not interfere with the immunogenic response to BNT162b2 vaccine in patients with SpA; however, TNFi therapy was associated with lower S1/S2-antibody titers, faster decline, and higher rate of breakthrough infections.

Circulating and Synovial Monocytes in Arthritis and Ex-Vivo Model to Evaluate Therapeutic Modulation of Synovial Monocytes.

Monocytes are innate immune cells that play a dual role in protection of host against pathogens and initiation and perpetuation of inflammatory disorders including joint diseases. During inflammation, monocytes migrate from peripheral blood to tissues via chemokine receptors where they produce inflammatory factors. Monocytes are classified into three subsets, namely: classical, intermediate and non-classical, each subset has particular function. Synovium of patients with inflammatory joint diseases, such as rheumatoid arthritis and psoriatic arthritis as well as osteoarthritis, is enriched by monocytes that differ from circulatory ones by distinct subsets distribution. Several therapeutic agents used systemically or locally through intra-articular injections in arthritis management modulate monocyte subsets. This scoping review summarized the existing literature delineating the effect of common therapeutic agents used in arthritis management on circulating and synovial monocytes/macrophages. As certain agents have an inhibitory effect on monocytes, we propose to test their potential to inhibit synovial monocytes via an ex-vivo platform based on cultured synovial fluid mononuclear cells derived from patients with rheumatic diseases. Information obtained from the ex-vivo platform can be applied to explore the therapeutic potential of medications in clinical practice.

Synovial monocytes from psoriatic and rheumatoid arthritis patients are modulated differently by TNF inhibitors and glucocorticoids: an ex-vivo study.

OBJECTIVES: Synovial monocytes (expressing CD14+CD16+) affect pro-inflammatory responses in the synovium microenvironment of psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The effect of various drugs on those cells was evaluated. METHODS: Synovial fluid mononuclear cells (SFMCs) from PsA (n=29) and RA (n=11) patients were cultured with biologics or glucocorticoids (GCs). CD14+CD16+ cells were analysed by flow cytometry. TNF secretion was assessed by ELISA and changes in cytokine and matrix metalloproteinase-9 (MMP-9) mRNA by qPCR. RESULTS: TNF inhibitors (i) [adalimumab (ADA) and infliximab (IFX)] significantly reduced the %CD14+CD16+ cells (p<0.04 and p<0.02, respectively) compared to IL-17Ai, IL-12/23i, and GCs in PsA patients' SFMCs. Similarly, those TNFi reduced the %CD14+CD16+ cells (p<0.05 and p<0.02, respectively) compared to IL-6Ri, CD20i and GCs in RA patients' SFMCs. TNFi (ADA p<0.01, IFX p=0.0003), and GCs (p<0.05) reduced TNF levels in PsA patients SFMCs supernatants. IFX down-regulated IL-1ß mRNA (p<0.005) while GCs betamethasone (BET) (p<0.01) and methylprednisolone acetate (MPA) (p<0.005) led to IL-1ß up-regulation. IFX down-regulated IL-8 and MMP-9 (p<0.01) and up-regulated IL-10 (p<0.005), and GCs did so to a greater extent (for IL-8, BET p<0.0001 and MPA p<0.005, for MMP-9, BET and MPA p<0.0001 and for IL-10, BET and MPA p<0.0001). CONCLUSIONS: TNFi but not GCs reduced the inflammatory monocytes. Both TNFi and GCs inhibited TNF secretion but differently modulated IL-1ß, IL-8, MMP-9 and IL-10 gene expression. Our data point to TNFi as a modulator of synovial monocytes.

Systemic Lupus Erythematous and Obstructive Sleep Apnea: A Possible Association.

Marked fatigue is common in patients with systemic lupus erythematosus (SLE). This study aimed to assess the association of sleep disorders, including obstructive sleep apnea (OSA), with SLE. Forty-two consecutive patients with SLE and 20 healthy controls were recruited and underwent a one-night ambulatory sleep examination. They completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI) and Functional Assessment of Chronic Illness Therapy (FACIT). SLE disease activity and damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI). A significantly increased apnea/hypopnea index was noted in the SLE group compared to healthy controls (p = 0.004). SLE patients had higher rates of moderate-to-severe OSA (p = 0.04), PSQI (p = 0.001), and FACIT scores (p = 0.0008). Multivariate analysis revealed that the SDI was associated with OSA (p = 0.03). There was a positive association between SLEDAI-2K and moderate-to-severe OSA (p = 0.03). Patients with SLE had an increased prevalence of OSA and poorer quality of sleep compared to healthy controls. Our findings suggest that active disease and accumulated damage may be associated with OSA. These findings highlight the importance of identifying the presence of OSA in patients with SLE.

Sex differences in the efficacy, safety and persistence of patients with psoriatic arthritis treated with tofacitinib: a post-hoc analysis of phase 3 trials and long-term extension.

BACKGROUND: Evaluate the impact of sex on tofacitinib efficacy, safety and persistence (time to discontinuation) in patients with psoriatic arthritis (PsA). METHODS: Data were pooled from two phase 3 randomised controlled trials. Patients were randomised to tofacitinib 5 mg or 10 mg two times per day, adalimumab 40 mg every 2 weeks or placebo. Efficacy outcomes to month 12 included American College of Rheumatology (ACR)20/50/70, minimal disease activity (MDA), Psoriasis Area Severity Index (PASI)75, change from baseline (∆) in Health Assessment Questionnaire-Disability Index (HAQ-DI) and ∆Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Safety was assessed to month 12 and persistence was assessed to month 42 of a long-term extension study. RESULTS: Overall, 816 patients were included (54.3% females). At baseline, higher tender joint counts, enthesitis scores and worse HAQ-DI and FACIT-F were reported in females versus males; presence of dactylitis and PASI were greater in males versus females. At month 3, tofacitinib efficacy generally exceeded placebo in both sexes. Overall, similar ACR20/50/70, PASI75, ∆HAQ-DI and ∆FACIT-F were observed for tofacitinib between sexes; females were less likely to achieve MDA. Similar proportions of males/females receiving tofacitinib (both doses) experienced treatment-emergent adverse events (AEs). Serious AEs occurred in 3.4%/6.6% and 4.0%/5.9% males/females with tofacitinib 5 mg and 10 mg two times per day. Persistence was generally similar between sexes. CONCLUSION: Tofacitinib efficacy exceeded placebo in both sexes and was comparable between sexes. Consistent with previous studies of PsA treatments, females were less likely to achieve MDA, likely due to baseline differences. Safety and time to discontinuation were generally similar between sexes. TRIAL REGISTRATION NUMBER: NCT01877668; NCT01882439; NCT01976364.

Sex-Based Differences in Sonographic and Clinical Findings Among Patients With Psoriatic Arthritis.

OBJECTIVE: To investigate sex-based sonographic differences in patients with psoriatic arthritis (PsA). METHODS: The study population included consecutive prospectively recruited patients with PsA, as determined by the CASPAR (Classification for Psoriatic Arthritis) criteria, who underwent clinical and physical examinations, followed by a detailed ultrasound (US) evaluation (greyscale and Doppler). US evaluation included 52 joints, 40 tendons, and 14 points of entheses (Modified Madrid Sonographic Enthesis Index [MASEI] plus lateral epicondyles) performed by an experienced sonographer blinded to the clinical data. The US score was based on the summation of a semiquantitative score for synovitis, tenosynovitis, and enthesitis. The US enthesitis score was categorized into inflammatory lesions (ie, hypoechogenicity, thickening, bursitis, and Doppler) and structural lesions (ie, enthesophytes/calcifications and erosions). RESULTS: The study population of 158 patients included 70 males and 88 females. The males had higher rates of employment (P = 0.01), Psoriasis Area and Severity Index scores (P = 0.04), and mean swollen joint counts (P = 0.04). The total US score and its subcategory scores-the synovitis and tenosynovitis scores-were similar for both sexes, whereas the total enthesitis score and its subcategory score-the inflammatory enthesitis score-were significantly higher for the males compared to the females (P = 0.01 and P = 0.005, respectively). Hypoechogenicity, thickening, and enthesophytes were more prevalent in males compared to females (P < 0.05). Multivariate ordinal logistic regression models showed that male sex was associated with a higher US inflammatory enthesitis score compared to female sex (odds ratio 1.96, P = 0.02). CONCLUSION: Sonographic enthesitis was more prevalent in males compared to females with PsA. These differences were not reflected by enthesitis disease activity scores derived from clinical assessment.

Management of Dactylitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: This literature review aimed to identify the most efficacious current interventions for dactylitis and provide up-to-date scientific evidence to support the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations on the management of psoriatic arthritis. METHODS: Original articles published from 2013 to 2020, registered in MEDLINE, Embase, and Cochrane Library, describing interventional trials and reporting dactylitis-related outcomes were included. The 20 members of the GRAPPA dactylitis group were divided into 9 subgroups according to treatment, and members of each group independently extracted data from articles/abstracts corresponding to their group by using a standardized data extraction form. RESULTS: Forty-nine publications were analyzed, representing 40 randomized clinical trials (RCTs) and including 16,752 patients. Dactylitis was assessed as a secondary outcome in 97.5% of these trials and more than 40% of RCTs did not employ a specific dactylitis measure or instrument. CONCLUSION: The emergence of agents with novel mechanisms of action in recent years, such as interleukin 17 (IL-17), IL-12/23, IL-23, and Janus kinase inhibitors, has significantly expanded the available treatment options for dactylitis. This article points out the lack of consensus regarding dactylitis assessment and the paucity of data concerning the effect of local steroid injections, nonsteroidal antiinflammatory drugs, and conventional disease-modifying antirheumatic drugs. Clinical trials evaluating the effect of these traditional and low-cost medications used to treat dactylitis should be encouraged.

Immunogenicity induced by two and three doses of the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases and immunocompetent controls: a longitudinal multicentre study.

OBJECTIVES: To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls. METHODS: A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample. RESULTS: The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1. CONCLUSIONS: The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients.

Predictors of Immunogenic Response to the BNT162b2 mRNA COVID-19 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases Treated with Rituximab.

Treatment with rituximab (RTX) blunts SARS-CoV-2 vaccination-induced humoral response. We sought to identify predictors of a positive immunogenic response to the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD) treated with RTX (AIIRD-RTX). We analyzed 108 AIIRD-RTX patients and 122 immunocompetent controls vaccinated with BNT162b2 mRNA participating in a multicenter vaccination study. Immunogenicity was defined by positive anti-SARS-CoV-2 S1/S2 IgG. We used a stepwise backward multiple logistic regression to identify predicting factors for a positive immunogenic response to vaccination and develop a predicting calculator, further validated in an independent cohort of AIIRD-RTX BNT162b2 mRNA vaccinated patients (n = 48). AIIRD-RTX patients who mounted a seropositive immunogenic response significantly differed from patients who did not by a lower number of RTX courses (median (range) 3 (1-10) vs. 5 (1-15), p = 0.007; lower cumulative RTX dose (mean ± SD) 6943.11 ± 5975.74 vs. 9780.95 ± 7240.12 mg, p = 0.033; higher IgG level prior to last RTX course (mean ± SD), 1189.78 ± 576.28 vs. 884.33 ± 302.31 mg/dL, p = 0.002), and extended interval between RTX treatment and vaccination, 469.82 ± 570.39 vs. 162.08 ± 160.12 days, p = 0.0009, respectively. Patients with ANCA-associated vasculitis and inflammatory myositis had a low likelihood of a seropositive immunogenic response compared to patients with rheumatoid arthritis, odds ratio (OR) 0.209, 95% confidence interval (CI) 0.046-0.96, p = 0.044 and OR 0.189, 95% CI 0.036-0.987, p = 0.048, respectively. Based on these findings, we constructed a calculator predicting the probability of a seropositive immunogenic response following BNT162b2 mRNA vaccination which performed with 90.5% sensitivity, 59.3% specificity, and 63.3% positive and 88.9% negative predictive values. In summary, the predicting calculator could guide clinicians for optimal timing of BNT162b2 mRNA vaccination in AIIRD-RTX patients.

Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatment response in autoimmune diseases.

Regulatory T cells (Tregs) comprise a CD4+CD25+Foxp3+ T cell subset for maintaining immune tolerance, and their deficits and/or dysfunction are observed in autoimmune diseases. The lymphocyte activation gene 3 (LAG-3, also known as CD223), which is an immunoglobulin superfamily member expressed on peripheral immune cells, is recognized as an inhibitory regulator of Tregs. LAG-3+ T cells represent a novel protective Tregs subset that produces interleukin-10. Alterations in LAG-3+ Tregs have been reported in several autoimmune diseases, suggesting their potential pathogenic role. Recent studies have indicated that LAG-3+ Tregs may be associated not only with immunopathology but also with response to therapy in several autoimmune and autoinflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis and others. We present a review of Tregs phenotypes and functions, with a focus on LAG-3+ Tregs, and discuss their potential role as biomarkers for treatment response in autoimmune diseases.

T cell functions of psoriatic arthritis patients are regulated differently by TNF, IL-17A and IL-6 receptor blockades in vitro.

OBJECTIVES: The impact of biologics used in PsA management on T cells is unknown. This study evaluated the effect of tumour necrosis factor-alpha (TNFα), interleukin-17A (IL-17A), and IL-6 receptor (IL-6R) blockers on T cell function in PsA patients and healthy controls peripheral blood mononuclear cells (PBMCs). METHODS: A total of 111 PsA patients and 32 healthy controls were recruited. PBMCs were co-cultured in presence of the biologics. T cell activation and proliferation were analysed by flow cytometry and cytokines in supernatants were measured by ELISA. The effect of biologics on lymphocyte proliferation was determined in response to phytohemagglutinin (PHA). RESULTS: Activated CD4+CD25+ T cells were significantly reduced by adalimumab (ADA) in PsA patients as compared to medium, ixekizumab (IXE), and tocilizumab (TCZ), while in healthy controls, ADA reduced the activated CD4+CD25+ T cells non-significantly. Elevated TNFα and IL-1ß levels were produced in supernatants of PsA patients as compared to healthy controls. TNFα, IL-17A, IL-1ß, and MMP-3 levels were reduced by ADA compared to medium (p<0.0001, p<0.0004, p<0.04, p<0.04, respectively). IXE reduced IL-17A (p<0.0001) but not the other cytokines. ADA had higher susceptibility to inhibit PHA-induced proliferation in both PsA patients and healthy controls (p<0.03) as compared to IXE and TCZ. CONCLUSIONS: Both TNF and IL-17A blockers are suitable for PsA treatment, but exhibit different activity on T cells. Moreover, the study reveals part of the mechanism exerted by ADA and provides a possible explanation for TCZ inefficacy in PsA.

Ultrasound, magnetic resonance imaging and radiography of the finger joints in psoriatic arthritis patients.

OBJECTIVES: To report the discrepancies and agreements between US, MRI and radiography of the hand in PsA, and to compare the sensitivity and specificity of US and radiography to MRI as the gold standard imaging study in PsA. METHODS: All of the 100 prospectively recruited consecutive PsA patients underwent clinical assessment and concomitant radiographic, US and MRI studies of the MCP, PIP and DIP joints of one hand. Synovitis, flexor tenosynovitis, extensor paratenonitis, erosions and bone proliferations were identified and scored. All readers were blinded to clinical data, and agreement was calculated based on prevalence-adjusted bias-adjusted kappa (PABAK). RESULTS: The prevalence of synovitis, flexor tenosynovitis, extensor paratenonitis and erosions was similar for US and MRI, while that of bone proliferation was significantly increased in US and radiography compared with MRI (P < 0.001). The absolute agreement between US and MRI was good-to-very good for synovitis (85-96%, PABAK = 0.70-0.92), flexor tenosynovitis (93-98%, PABAK = 0.87-0.96) and extensor paratenonitis (95-98%, PABAK = 0.90-0.97). Agreement between US, MRI and radiography was 96-98% (PABAK = 0.92-0.97) for erosions and 71-93% (PABAK = 0.47-0.87) for bone proliferations. Sensitivity of US with MRI as gold standard was higher for synovitis (0.5-0.86) and extensor paratenonitis (0.63-0.85) than for flexor tenosynovitis (0.1-0.75), while the specificity was high for each pathology (0.89-0.98). CONCLUSION: There is very good agreement between US and MRI for the detection of inflammatory changes in finger joints in PsA. US, radiography and MRI have a good-to-very good agreement for destructive changes.

Seroprevalence of SARS-CoV-2 antibodies in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: To assess the prevalence of anti-SARS-CoV-2 antibodies in autoimmune inflammatory rheumatic disease (AIIRD) patients, and to define clinical factors associated with seropositivity. METHODS: A cross sectional study was conducted at a tertiary rheumatology department in Israel. Consecutive patients completed a questionnaire and were tested for SARS-CoV-2 anti-nucleoprotein IgG (N-IgG). If this was positive, an anti-S1/S2 spike IgG (S-IgG) test was done. If both were positive, the patient was considered seropositive. Seropositive patients were retested after 3 months. RESULTS: The study included 572 AIIRD patients. Thirty patients were found seropositive, for a seroprevalence of 5.24%. The seropositive rate was significantly lower for patients treated with immunosuppressive medications (3.55%, p≤0.01), and specifically for patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) (2.7%, p≤0.05). These associations remained significant in the multivariate regressions adjusting for age, sex and exposure to a known COVID-19 patient. A second serology test 3 months later was collected in 21 of the 30 seropositive patients. In a mean±standard deviation (SD) of 166.63±40.76 days between PCR and second serology, 85% were still positive for N-IgG, and 100% were still positive for S-IgG, with a higher mean±SD titre compared to the first S-IgG (166.77±108.77 vs. 132.44±91.18, respectively, p≤0.05). CONCLUSIONS: Humoral response to SARS-CoV-2 in AIIRD patients may be affected be immunosuppressive treatment, especially bDMARDs. In patients with AIIRD, titres of SARS-CoV-2 IgG antibodies, especially N-IgG antibodies, fade with time, while S-IgG antibodies persist.

CD4+ LAG-3+ T cells are decreased in active psoriatic arthritis patients and their restoration in vitro is mediated by TNF inhibitors.

Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with T cell dysregulation. The lymphocyte-activation gene (LAG)-3 is one of the regulatory receptors expressed on T cells in a soluble form. LAG-3 expression on T cells was analyzed in vitro in PsA patients with minimal disease activity (MDA), active disease (non-MDA) and healthy controls. In cultured in-vitro peripheral blood mononuclear cells (PBMCs), LAG-3 expression on CD4+ T cells was similar in both MDA PsA patients (7.5 ± 0.9) (n = 14) and healthy controls (7.8 ± 0.6) (n = 15), but significantly lower in non-MDA PsA patients (3.1 ± 0.3) (n = 13) (p < 0.0001). An inverse correlation between PsA clinical disease activity and %CD4+ LAG-3+ T cells in vitro was observed (composite psoriatic disease activity index r = -0.47, p < 0.02 and psoriatic arthritis disease activity score, r = -0.51, p < 0.008). In-vitro co-culture of CD4+ T cells with anti-tumor necrosis factor (TNF) or anti-interleukin (IL)-17A had no effect on LAG-3+ expression in MDA PsA patients and healthy controls. In non-MDA patients, anti-TNF, but not anti-IL-17A, restored the %CD4+ LAG-3+ T cells (7.9 ± 0.9 and 3.2 ± 0.4, respectively) (p < 0.0004). Lower soluble LAG-3 levels were found in sera of naive to biological PsA patients (n = 39) compared to healthy controls (n = 35) (p < 0.03). Impaired LAG-3 on CD4+ T cells may reflect active PsA disease state. Anti-TNFs have potency to up-regulate the CD4+ LAG-3+ T cells in vitro.

Role of ultrasound for assessment of psoriatic arthritis patients with fibromyalgia.

OBJECTIVE: To investigate whether ultrasonography (US), as an objective imaging modality, can optimise the evaluation of disease activity in psoriatic arthritis (PsA) patients with concomitant fibromyalgia syndrome (FMS). METHODS: The study population included 156 consecutive PsA patients who were recruited prospectively and fulfilled the ClASsification criteria for Psoriatic ARthritis criteria. The patients underwent complete clinical evaluation including assessment of fulfilment of the 2016 fibromyalgia classification criteria. All of the patients underwent US evaluation including 52 joints, 40 tendons and 14 entheses. The US score was based on the summation of a semiquantitative score (including synovitis, tenosynovitis and enthesitis). Scoring was performed by a sonographer blinded to the clinical data. Spearman's correlation coefficient and multivariate linear regression models were used to examine the association of FMS with clinical and the US scores. RESULTS: Forty-two patients (26.9%) with coexisting PsA and FMS were compared with 114 (73.1%) PsA patients without FMS. Patients with PsA and FMS had significantly increased scores for clinical composite indices, including non-Minimal Disease Activity, Composite Psoriatic Disease Activity Index (CPDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS) (p<0.001). In contrast, the total US score and its subcategories were similar for those with and without FMS. The total US score significantly correlated with CPDAI, DAPSA and PASDAS (p<0.001) in the PsA without FMS but not in the PsA with FMS group. FMS was significantly associated with higher clinical scores (p<0.001) but not with the US score (multivariable linear regression models). CONCLUSIONS: US has significantly greater value than composite clinical scores in the assessment of disease activity in PsA patients with FMS.

Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study.

INTRODUCTION: Vaccination represents a cornerstone in mastering the COVID-19 pandemic. Data on immunogenicity and safety of messenger RNA (mRNA) vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) are limited. METHODS: A multicentre observational study evaluated the immunogenicity and safety of the two-dose regimen BNT162b2 mRNA vaccine in adult patients with AIIRD (n=686) compared with the general population (n=121). Serum IgG antibody levels against SARS-CoV-2 spike S1/S2 proteins were measured 2-6 weeks after the second vaccine dose. Seropositivity was defined as IgG ≥15 binding antibody units (BAU)/mL. Vaccination efficacy, safety, and disease activity were assessed within 6 weeks after the second vaccine dose. RESULTS: Following vaccination, the seropositivity rate and S1/S2 IgG levels were significantly lower among patients with AIIRD versus controls (86% (n=590) vs 100%, p<0.0001 and 132.9±91.7 vs 218.6±82.06 BAU/mL, p<0.0001, respectively). Risk factors for reduced immunogenicity included older age and treatment with glucocorticoids, rituximab, mycophenolate mofetil (MMF), and abatacept. Rituximab was the main cause of a seronegative response (39% seropositivity). There were no postvaccination symptomatic cases of COVID-19 among patients with AIIRD and one mild case in the control group. Major adverse events in patients with AIIRD included death (n=2) several weeks after the second vaccine dose, non-disseminated herpes zoster (n=6), uveitis (n=2), and pericarditis (n=1). Postvaccination disease activity remained stable in the majority of patients. CONCLUSION: mRNA BNTb262 vaccine was immunogenic in the majority of patients with AIIRD, with an acceptable safety profile. Treatment with glucocorticoids, rituximab, MMF, and abatacept was associated with a significantly reduced BNT162b2-induced immunogenicity.