Foreword: Seminars in Research 2014 Joint Experiences in Rheumatology and Dermatology

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Effect of Etanercept on anti-carbamylated protein antibodies in patients with rheumatoid arthritis

Rheumatoid Arthritis (RA) is a systemic, chronic inflammatory disease characterized by inflammation of synovial joints and production of autoantibodies such as Rheumatoid Factor and antibodies directed against modified proteins - i.e. anti-citrullinated peptides antibody (ACPA). Carbamylation, as a post translational modification, has been recently associated to RA since anti-carbamylated protein antibodies (anti-CarP) have been detected in the sera of RA patients. The effect of treatment on anti-CarP level has been never addressed before. Through this study we aimed to investigate the short term effect of anti-TNF treatment with Etanercept on anti-CarP. We enrolled consecutive RA patients before starting treatment with Etanercept. Clinical data and serum samples were gathered from each patient at baseline and after 3 months of treatment. Disease activity was assessed at baseline and after 3 months by using the C-reactive protein - Disease Activity Score (DAS) 28. Sixty-three age and sex matched healthy donors served as controls. Anti-Car-P antibodies were investigated by immune-enzymatic assay. We enrolled 17 RA patients (F:M 15:2, mean age 44.1 ± 10.7 years, mean disease duration 7.9 ± 5.8 years). Six patients (35.3%) were positive for anti-CarP antibodies at baseline while three months after only 4 patients (23.5%) remained positive. Mean serum level of anti-CarP antibodies at baseline and after 3 months were: 253.0 ± 139.8AU/ml and 271.0 ± 132.4AU/ml respectively. Considering the persistently anti-CarP positive patients, the mean antibody titre increases from 386.2 ± 49.3AU/ml at baseline to 421.8 ± 144.0AU/ml at follow up. The effect of anti-TNF treatment on autoantibody status is still controversial; in particular, data on ACPA variation during treatment are discordant. In our cohort of long standing RA patients, a short term course of Etanercept did not affect the anti-CarP status. In conclusion, this pilot study demonstrated a slight reduction in the percentage of anti-CarP positive patients but an overall increase of antibody titres unrelated to the clinical response to TNF blockade was observed

HiJAKing SARS-CoV-2? The potential role of JAK inhibitors in the management of COVID-19.

JAK kinase inhibitors are being investigated as a way of managing cytokine storm in patients with severe COVID-19

Response to 'Is there a future for hydroxychloroquine/chloroquine in prevention of SARS-CoV-2 infection (COVID-19)?' by Moiseev <i>et al</i>

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Reprint of "Anti-therapeutic antibodies and their clinical impact in patients treated with the TNF antagonist adalimumab".

Highlights • ECL-based assays for measurement of adalimumab and adalimumab antibodies. • Performance of ECL antibody assay not significantly improved by acid dissociation. • Negative correlation between levels of antibody and free adalimumab. • Negative correlation between adalimumab level and disease activity scores

Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients

BACKGROUND: Rheumatoid arthritis (RA) patients carry a high risk of cardiovascular morbidity and mortality. The excess of cardiovascular disease cannot be entirely explained by traditional risk factors and the immune system contributes to the development of atherosclerosis. Moreover, post-translational modifications such as citrullination and carbamylation have been linked to inflammation and atherosclerosis. Anti-carbamylated proteins antibodies (anti-CarP) are a new subset of autoantibodies identified in RA patients. This study aimed to investigate a possible association between anti-CarP and subclinical atherosclerosis in RA patients. METHODS: We enrolled RA patients and normal healthy controls (NHS) without known cardiovascular risk factors or heart disease. Cardiovascular risk was assessed using the Modified Systemic Coronary Risk Evaluation (mSCORE). Anti-CarP were investigated by a solid phase "home-made" ELISA. Anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF) were investigated by ELISA assays. Subclinical atherosclerosis was evaluated by brachial artery Flow-Mediated Dilatation (FMD) and Carotid Intima-Media Thickness (c-IMT) while arterial stiffness by Ankle-Brachial Index (ABI) and Cardio-Ankle Vascular Index (CAVI). RESULTS: We enrolled 50 RA patients (34 F and 16 M, mean age 58.4 ± 13.1 years, mean disease duration 127 ± 96.7 months) and 30 age and sex matched NHS. According to the mSCORE, 58% of patients had a low risk, 32% a moderate and 8% a high risk for cardiovascular disease. FMD was significantly lower in RA patients than in NHS (5.6 ± 3.2 vs 10.7 ± 8.1%; p < 0.004) and CAVIs significantly higher in a RA patients compared to NHS (left CAVI 8.9 ± 1.7 vs 8.1 ± 1.5; p < 0.04 for and right CAVI 8.8 ± 1.6 vs 8.0 ± 1.4; p < 0.04 for the). ABI and c-IMT did not differ between the two populations. The multivariate regression analysis showed a significant association of anti-CarP antibodies with FMD, left and right CAVI and both c-IMT (r = 1.6 and p = 0.05; r = 1.7 and p = 0.04; r = 2.9 and p = 0.05; r = 1.5 and p = 0.03; r = 1.1 and p = 0.03 respectively). CONCLUSIONS: This study confirms that RA patients, without evidence of cardiovascular disease or traditional risk factors, have an impaired endothelial function. Moreover, we found an association with anti-CarP antibodies suggesting a possible contribution of these autoantibodies to endothelial dysfunction, the earliest stage of atherosclerosis. Besides ultrasound assessment, anti-CarP should be assessed in RA patients and considered an additional cardiovascular risk factor

Systemic Lupus Erythematosus with and without Anti-dsDNA Antibodies: Analysis from a Large Monocentric Cohort

Objectives. The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70–98% of patients test positive. We evaluated the demographic, clinical, laboratory, and therapeutical features of a monocentric SLE cohort according to the antidsDNA status. Methods. We identified three groups: anti-dsDNA + (persistent positivity); anti-dsDNA ± (initial positivity and subsequent negativity during disease course); anti-dsDNA − (persistent negativity). Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM). Results. We evaluated 393 patients (anti-dsDNA +: 62.3%; anti-dsDNA ±: 13.3%; anti-dsDNA −: 24.4%). The renal involvement was signifiantly more frequent in anti-dsDNA + (30.2%), compared with antidsDNA ± and anti-dsDNA − (21.1% and 18.7%, resp.; = 0.001). Serositis resulted signifiantly more frequent in anti-dsDNA − (82.3%) compared to anti-dsDNA + and anti-dsDNA ± (20.8% and 13.4%, resp.; < 0.0001). Th reduction of C4 serum levels was identified significantly more frequently in anti-dsDNA + and anti-dsDNA ± (40.0% and 44.2%, resp.) compared with antidsDNA − (21.8%, = 0.005). We did not identify significant differences in the mean ECLAM values before and after modifiation of anti-dsDNA status ( = 0.7). Conclusion. Anti-dsDNA status influences the clinical and immunological features of SLE patients. Nonetheless, it does not appear to affect disease activity

Cognitive dysfunction improves in systemic lupus erythematosus: Results of a 10 years prospective study

Objective Cognitive impairment (CI) has been described in 3–80% of Systemic lupus erythematosus (SLE) patients but only short-term studies evaluated its over-time changes, suggesting that CI is usually a stable finding. We aimed at evaluating the changes of SLE-related CI in a 10-years prospective single center cohort study. Methods We evaluated 43 patients (M/F 5/38; mean age = 45.7±10.1 years; mean disease duration = 230.8±74.3 months) at baseline (T0) and after 10 years (T1). A test battery designed to detect fronto-subcortical dysfunction across five domains (memory, attention, abstract reasoning, executive and visuospatial function) was administered. A global cognitive dysfunction score (GCD) was obtained and associated with clinical and laboratory features. Results Prevalence of CI was 20.9% at T0 and 13.9% at T1 (P = NS). This impairment was prevalently mild at T0 (55.5%) and mild or moderate at T1 (36.3% for both degrees). After 10 years, CI improved in 50% of patients, while 10% worsened. Impaired memory (P = 0.02), executive functions (P = 0.02) and abstract reasoning (P = 0.03) were associated with dyslipidemia at T0. Worsening of visuospatial functions was significantly associated with dyslipidemia and Lupus Anticoagulant (P = 0.04 for both parameters). Finally, GCD significantly correlated with chronic damage measured by SLICC/damage index at T0 (r = 0.3; P = 0.04) and T1 (r = 0.3; P = 0.03). Conclusions For the first time, we assessed CI changes over 10-years in SLE. CI improved in the majority of the patients. Furthermore, we observed an improvement of the overall cognitive functions. These results could suggest that an appropriate management of the disease during the follow-up could be able to control SLE-related CI

Autophagy and rheumatoid arthritis: Current knowledges and future perspectives

Autophagy is a degradation mechanism by which cells recycle cytoplasmic components to generate energy. By influencing lymphocyte development, survival, and proliferation, autophagy regulates the immune responses against self and non-self antigens. Deregulation of autophagic pathway has recently been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA). Indeed, autophagy seems to be involved in the generation of citrullinated peptides, and also in apoptosis resistance in RA. In this review, we summarize the current knowledge on the role of autophagy in RA and discuss the possibility of a clinical application of autophagy modulation in this disease

TNFα expressed on the surface of microparticles modulates endothelial cell fate in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is associated with a high prevalence of atherosclerosis. Recently increased levels of microparticles (MPs) have been reported in patients with RA. MPs could represent a link between autoimmunity and endothelial dysfunction by expressing tumor necrosis factor alpha (TNFα), a key cytokine involved in the pathogenesis of RA, altering endothelial apoptosis and autophagy. The aim of this study was to investigate TNFα expression on MPs and its relationship with endothelial cell fate. Methods: MPs were purified from peripheral blood from 20 healthy controls (HC) and from 20 patients with RA, before (time (T)0) and after (T4) 4-month treatment with etanercept (ETA). Surface expression of TNFα was performed by flow cytometry analysis. EA.hy926 cells, an immortalized endothelial cell line, were treated with RA-MPs purified at T0 and at T4 and also, with RA-MPs in vitro treated with ETA. Apoptosis and autophagy were then evaluated. Results: RA-MPs purified at T0 expressed TNFα on their surface and this expression significantly decreased at T4. Moreover, at T0 RA-MPs, significantly increased both apoptosis and autophagy levels on endothelial cells, in a dose-dependent manner. RA-MPs did not significantly change these parameters after 4 months of in vivo treatment with ETA. Conclusions: Our data demonstrate that MPs isolated from patients with RA exert a pathological effect on endothelial cells by TNFα expressed on their surface. In vivo and in vitro treatment with ETA modulates this effect, suggesting anti-TNF therapy protects against endothelial damage in patients with RA