Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

The effects of pancaspase-inhibitor zVAD-FMK on macrophage and lymphocyte apoptosis

Grundlagen: Die intrazelluläre Aktivierung von Caspasen ist ein Schlüsselereignis der Apoptose. zVAD-FMK ist ein in der Forschung häufig als Apoptosehemmstoff verwendeter Pancaspase-Inhibitor, der u.a. dazu genutzt wurde, die T-Zellapoptose zu blockieren. Verhalten und Überleben der T-Zellen werden maßgeblich von antigenpräsentierenden Zellen, insbesondere den Makrophagen beeinflusst. Ziel: Die Wirkung von zVAD-FMK auf das Apoptoseverhalten der Makrophagen sollte untersucht werden. Dabei wurde die Hypothese geprüft, ob zVAD-FMK durch Apoptose von Makrophagen die T-Zellantwort beeinflusst. Zusätzlich sollten Unterschiede im Apoptoseverhalten zwischen Zellen von Neugeborenen und Erwachsenen aufgedeckt werden. Material und Methoden: Aus Nabelschnurblut (NSB) und peripherem Blut von gesunden Erwachsenen (PB) wurden mononukleäre Zellen isoliert, mit zVAD-FMK inkubiert und mit dem T-Zellmitogen OKT3, einem monoklonalen Antikörper gegen CD4 (ch412), Lipopolysaccharid (LPS) sowie Kombinationen aus Lipopolysaccharid (LPS) und Interferon-gamma (IFNgamma) stimuliert. Die Apoptoserate wurde durchflusszytometrisch mit Annexin V und Propidiumiodid bestimmt. Parallel wurde der Phänotyp von Makrophagen und T-Zellen analysiert. Ergebnisse: zVAD-FMK führte spezifisch zur Abnahme der Makrophagenzahl um 50% (p < 0.05). Verbleibende Makrophagen erschienen mit verminderter Zellgröße und erhöhter Granularität. Der 'Schrumpfungszelltod' wurde durch die signifikant erhöhte Anfärbung mit Annexin V und Propidiumiodid als Apoptose bestätigt. Kinetiken ergaben, dass die Hälfte der Makrophagen innerhalb von 24 Stunden unter gleichzeitiger Herabregulation von CD14 um 80% apoptotisch wurden. Makrophagen aus NSB und PB unterschieden sich nicht in ihrer Reaktion auf zVAD-FMK. Die Expression von B7-Molekülen und HLA-DR blieben unverändert, während die Expression von MHC Klasse I-Molekülen und der Anteil CD16 exprimierender Makrophagen durch die Caspase-Inhibition abnahm. Phänotyp und Überleben der Lymphozyten (T-, B-, NK-Zellen) blieben dagegen unbeeinträchtigt. CD95 und CD95Ligand wurden durch zVAD-FMK weder auf Makrophagen noch Lymphozyten reguliert. Aktivierung der Makrophagen mit Lipopolysaccharid konnte ihre Apoptose nicht verhindern. Ihr Zelltod durch OKT3 wurde verstärkt, während die OKT3-bedingte T-Zelldeletion durch zVAD-FMK vollständig verhindert wurde. T-Zellproliferation und die Aufregulation von CD28 durch OKT3 wurden gehemmt. Die Apoptose der CD4-T-Zellen durch ch412 konnte mit zVAD-FMK um 50% reduziert werden bei gleichzeitiger Abnahme der Makrophagenzahl. Schlussfolgerung: zVAD-FMK induzierte Apoptose in Makrophagen und beeinflusste dadurch makrophagenvermittelte T-Zellreaktionen. Ob diese Wirkung durch die Caspasehemmung selbst oder durch Interaktion mit anderen Molekülen verursacht wurde, bleibt zu untersuchen.Background: The intracellular activation of caspases is a key event in apoptosis. zVAD-FMK is an inhibitor of the caspase family often used in research to block e.g. T cell apoptosis. T cell reactions and -survival are orchestrated by antigen presenting cells such as macrophages. Aim: To investigate the effect of zVAD-FMK on macrophages and to test the hypothesis, whether it influences T cell reactions via macrophage apoptosis. In addition to discover differences between apoptosis of neonatal and adult cells. Material and methods: Mononuclear cells were isolated from cord blood (CB) and peripheral blood of healthy adults (PB), cultured with zVAD-FMK and stimulated with the T cell mitogen OKT3, a monoclonal CD4-antibody (ch412), lipopolysaccharide (LPS) or combinations of lipopolysaccharide (LPS) and Interferon-gamma (IFNgamma). Apoptosis was measured by flow cytometry using Annexin V and propidium iodide. Further on phenotypic analysis of macrophages and lymphocytes was performed. Results: zVAD-FMK led to a specific decrease of 50% in macrophage count (p < 0.05). Remaining macrophages appeared with reduced size and increased granularity indicating 'schrinking death', which was confirmed as apoptosis by a significantly increased uptake of Annexin V and propidium iodide. Kinetics revealed apoptosis of half the macrophages within 24 hours accompanied by a downregulation of CD14 macrophage-receptors to 20%. Macrophages in CB and PB did not differ in their sensitivity towards zVAD-FMK. B7- and HLA DR-expression was unaffected by caspase inhibition, whereas MHC class I-expression and the number of CD16-expressing macrophages decreased. Lymphocyte phenotype and survival (T-, B-, NK-cells) remained unaffected. CD95- and CD95L-expression was not changed by zVAD-FMK neither on macrophages nor on lymphocytes. LPS-activation did not prevent zVAD-FMK-induced macrophage apoptosis. zVAD-FMK increased OKT3-mediated macrophage death, whereas OKT3-mediated T cell deletion was completely prevented. OKT3-induced T cell proliferation and upregulation of CD28 were inhibited. zVAD-FMK reduced ch412-induced CD4-T cell apoptosis by 50% accompanied simultaneously by a decrease in macrophage count. Conclusion: zVAD-FMK initiated macrophage apoptosis thereby affecting macrophage-mediated T cell reactions. Whether this effect is induced by caspase inhibition itself or by interaction with cellular molecules remains to be investigated

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ABSTRACT. Objective. Rituximab (RTX) has been used successfully for the treatment of severe Jo1 antibody-associated antisynthetase syndrome. The aim of this retrospective study was to evaluate the effect of RTX in severe Jo1 antisynthetase syndrome and determine predictive factors for response. Methods. There were 61 patients with Jo1 antisynthetase syndrome identified; 18 of these received RTX. One patient was lost to followup. The remaining 17 patients and 30 out of 43 patients who were treated with conventional immunosuppressive (IS) drugs were followed for a mean of 35 months and 84 months, respectively. Results. Polymyositis/dermatomyositis (95%) and interstitial lung disease (ILD; 66%) were the dominant clinical manifestations. Detection of anti-Ro52 antibodies (43%) was significantly associated with acute-onset ILD (p = 0.016) with O 2 dependency, and patients with high concentrations of anti-Ro52 (20%) had the highest risk (p = 0.0005). Sixteen out of 18 patients (89%) showed a fast and marked response to RTX. Among those patients who were highly positive for anti-Ro52, response to RTX was seen in 7 out of 7 cases (100%), but no response to cyclophosphamide (n = 4), cyclosporine A (n = 3), azathioprine (n = 9), methotrexate (n = 5), or leflunomide (n = 2) was observed. One patient treated with RTX died of pneumonia. Conclusion. RTX is effective in the treatment of severe forms of Jo1 antisynthetase syndrome. In our retrospective study, the presence of high anti-Ro52 antibody concentrations predicts severe acute-onset ILD and nonresponse to IS drugs. In contrast to conventional IS, RTX is equally effective in patients with Jo1 antisynthetase syndrome, independent of their anti-Ro52 antibody status. (J Rheumatol Firs

Nailfold capillaroscopy characteristics of antisynthetase syndrome and possible clinical associations: Results of a multicenter international study

Objective. To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. Methods. We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures. Results. NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p &lt; 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. Conclusion. NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS

Timing of onset affects arthritis presentation pattern in antisynthetase syndrome

Objective To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). Methods The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). Results 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). Conclusion In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility

Timing of onset affects arthritis presentation pattern in antisyntethase syndrome

79To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD).nonenoneGonzález-Gay, Miguel A; Montecucco, Carlomaurizio; Selva-O'Callaghan, Albert; Trallero-Araguas, Ernesto; Molberg, Ovynd; Andersson, Helena; Rojas-Serrano, Jorge; Perez-Roman, Diana Isabel; Bauhammer, Jutta; Fiehn, Christoph; Neri, Rossella; Barsotti, Simone; Lorenz, Hannes M; Doria, Andrea; Ghirardello, Anna; Iannone, Florenzo; Giannini, Margherita; Franceschini, Franco; Cavazzana, Ilaria; Triantafyllias, Konstantinos; Benucci, Maurizio; Infantino, Maria; Manfredi, Mariangela; Conti, Fabrizio; Schwarting, Andreas; Sebastiani, Giandomenico; Iuliano, Annamaria; Emmi, Giacomo; Silvestri, Elena; Govoni, Marcello; Scirè, Carlo Alberto; Furini, Federica; Lopez-Longo, Francisco Javier; Martínez-Barrio, Julia; Sebastiani, Marco; Manfredi, Andreina; Bachiller-Corral, Javier; Sifuentes Giraldo, Walter Alberto; Cimmino, Marco A; Cosso, Claudio; Belotti Masserini, Alessandro; Cagnotto, Giovanni; Codullo, Veronica; Romano, Mariaeva; Paolazzi, Giuseppe; Pellerito, Raffaele; Saketkoo, Lesley Ann; Ortego-Centeno, Norberto; Quartuccio, Luca; Batticciotto, Alberto; Bartoloni Bocci, Elena; Gerli, Roberto; Specker, Christof; Bravi, Elena; Selmi, Carlo; Parisi, Simone; Salaffi, Fausto; Meloni, Federica; Marchioni, Enrico; Pesci, Alberto; Dei, Giulia; Confalonieri, Marco; Tomietto, Paola; Nuno, Laura; Bonella, Francesco; Pipitone, Nicolò; Mera-Valera, Antonio; Perez-Gomez, Nair; Gerzeli, Simone; Lopez-Mejias, Raquel; Matos-Costa, Carlo Jorge; Pereira da Silva, Jose Antonio; Cifrian, José; Alpini, Claudia; Olivieri, Ignazio; Blázquez Cañamero, María Ángeles; Rodriguez Cambrón, Ana Belén; Castañeda, Santos; Cavagna, LorenzoGonzález-Gay, Miguel A; Montecucco, Carlomaurizio; Selva-O'Callaghan, Albert; Trallero-Araguas, Ernesto; Molberg, Ovynd; Andersson, Helena; Rojas-Serrano, Jorge; Perez-Roman, Diana Isabel; Bauhammer, Jutta; Fiehn, Christoph; Neri, Rossella; Barsotti, Simone; Lorenz, Hannes M; Doria, Andrea; Ghirardello, Anna; Iannone, Florenzo; Giannini, Margherita; Franceschini, Franco; Cavazzana, Ilaria; Triantafyllias, Konstantinos; Benucci, Maurizio; Infantino, Maria; Manfredi, Mariangela; Conti, Fabrizio; Schwarting, Andreas; Sebastiani, Giandomenico; Iuliano, Annamaria; Emmi, Giacomo; Silvestri, Elena; Govoni, Marcello; Scirè, Carlo Alberto; Furini, Federica; Lopez-Longo, Francisco Javier; Martínez-Barrio, Julia; Sebastiani, Marco; Manfredi, Andreina; Bachiller-Corral, Javier; Sifuentes Giraldo, Walter Alberto; Cimmino, Marco A; Cosso, Claudio; Belotti Masserini, Alessandro; Cagnotto, Giovanni; Codullo, Veronica; Romano, Mariaeva; Paolazzi, Giuseppe; Pellerito, Raffaele; Saketkoo, Lesley Ann; Ortego-Centeno, Norberto; Quartuccio, Luca; Batticciotto, Alberto; Bartoloni Bocci, Elena; Gerli, Roberto; Specker, Christof; Bravi, Elena; Selmi, Carlo; Parisi, Simone; Salaffi, Fausto; Meloni, Federica; Marchioni, Enrico; Pesci, Alberto; Dei, Giulia; Confalonieri, Marco; Tomietto, Paola; Nuno, Laura; Bonella, Francesco; Pipitone, Nicolò; Mera-Valera, Antonio; Perez-Gomez, Nair; Gerzeli, Simone; Lopez-Mejias, Raquel; Matos-Costa, Carlo Jorge; Pereira da Silva, Jose Antonio; Cifrian, José; Alpini, Claudia; Olivieri, Ignazio; Blázquez Cañamero, María Ángeles; Rodriguez Cambrón, Ana Belén; Castañeda, Santos; Cavagna, Lorenz

Timing of onset affects arthritis presentation pattern in antisyntethase syndrome

OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility

Characteristics and outcomes of SARS-CoV-2 breakthrough infections among double-vaccinated and triple-vaccinated patients with inflammatory rheumatic diseases

Objective To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs).Methods Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients’ vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression.Results In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14–347) days in patients being double-vaccinated, and after 88 (range 14–270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p&lt;0.001). Mortality was 2% in unvaccinated, 1.8% in the double-vaccinated and 0.6% in triple-vaccinated patients. Compared with unvaccinated patients, double-vaccinated (OR 0.43, 95% CI 0.29 to 0.62) and triple-vaccinated (OR 0.13, 95% CI 0.08 to 0.21) patients showed a significant lower risk of COVID-19-related hospitalisation. Using multivariable analysis, the third vaccination was significantly associated with a lower risk for COVID-19-related death (OR 0.26; 95% CI 0.01 to 0.73).Conclusions Our cross-sectional data of COVID-19 infections in patients with IRD showed a significant reduction of hospitalisation due to infection in double-vaccinated or triple-vaccinated patients compared with those without vaccination and even a significant reduction of COVID-19-related deaths in triple-vaccinated patients. These data strongly support the beneficial effect of COVID-19 vaccination in patients with IRD.Trial registration number EuDRACT 2020-001958-21

Timing of onset affects arthritis presentation pattern in antisynthetase syndrome

Abstract OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility