Neutrophilic Activity Biomarkers (Plasma Neutrophil Extracellular Traps and Calprotectin) in Established Patients with Rheumatoid Arthritis Receiving Biological or JAK Inhibitors: A Clinical and Ultrasonographic Study.

INTRODUCTION: This study assesses the accuracy of neutrophil activation markers, including neutrophil extracellular traps (NETs) and calprotectin, as biomarkers of disease activity in patients with established rheumatoid arthritis (RA). We also analyse the relationship between NETs and various types of therapies as well as their association with autoimmunity. METHODS: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves. RESULTS: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants. CONCLUSION: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA.

Satisfaction and effectiveness of switching from intravenous to subcutaneous belimumab treatment in daily clinical practice.

BACKGROUND: In 2017, belimumab (BEL) was approved in subcutaneous (SQ) administration. The effectiveness after switching from intravenous (IV) to SQ and patient satisfaction in daily clinical practice has not been studied. During the pandemic, patient follow-up and treatment were significantly affected, and some patients need a change from IV to SQ. Our aim was to evaluate daily clinical practice satisfaction to SQ BEL therapy in patients previously treated IV BEL. We hypothesized that SQ BEL in SLE patients previously treated with IV BEL was similar in effectiveness and conferred higher satisfaction. METHODS: Observational, multicenter study, conducted in 7 reference centers in Catalonia. We included stable SLE patients (EULAR/ACR 2019) on treatment with SQ BEL and previous use of IV BEL (at least 3 months on IV BEL before switching). Since there are no well-validated tools for SQ BEL treatment satisfaction, we used RASQ-SQ, validated in patients with lymphoma who switched from IV Rituximab to SQ treatment, and modified for BEL treatment. RESULTS: Twenty-seven patients were included. The more prevalent clinical manifestations observed were related to the skin and joints and the patients had a mean baseline SLEDAI of 2.96 (SD 2.4) and SLICC score of 0.67 (SD 0.88). The median time from treatment with IV BEL before switching to SQ was 21 months (range). 84% of patients reported confidence in SQ BEL. 85.2% felt that treatment with SQ BEL was convenient or very convenient. 85% felt they had gained time with the change. 89% would recommend the SQ injection to other patients. Disease activity (mean SLEDAI) and remission rates remain stable after switching. No major new adverse effects were reported. CONCLUSIONS: Overall satisfaction, satisfaction with via of administration, and satisfaction with the time taken to receive BEL were higher for SQ BEL treatment. A switching SQ strategy is a reasonable alternative for BEL patients.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Synovial tissue features associated with poor prognosis in inflammatory arthritis.

BACKGROUND: Inflammatory arthritis encompasses a group of immune-mediated diseases characterized by chronic joint inflammation. Despite having pathogenic mechanisms in common, the prognosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and undifferentiated arthritis (UA) could be different regarding progression to chronic, to erosive, or to self-limited disease. Our aim was to evaluate the potential association of synovial tissue (ST) inflammatory cell infiltrate, the presence of ectopic lymphoid neogenesis (LN +) structures, and poor prognosis factors (PPF) in patients with RA, PsA, and UA. METHODS: We conducted a retrospective study including patients with active arthritis (RA, PsA, UA) who had ST obtained by rheumatological arthroscopy or ultrasound-guided biopsy. Clinical, demographic, and immunohistochemical data of the synovium was evaluated. Patients with biological therapy at the time of synovial biopsy were excluded. PPF in patients with RA and UA were defined by the presence of anti-cyclic citrullinated peptide antibodies and/or rheumatoid factor, development of bone erosions, or requirement of biological therapy during the follow-up. PPF in patients with PsA were defined as the presence of high levels of acute-phase reactants (ESR/CRP), dactylitis or nail involvement at the time of biopsy, development of bone erosion, or requirement of biological therapy during the follow-up. RESULTS: A total of 88 patients were included: 26 RA, 33 PsA, and 29 UA. All patients were followed up for 5 years after the biopsy. Fourteen (53.84%) RA patients had PPF, and 17 (65.38%) had LN + . LN + was associated with PPF (p 0.038) and biologic therapy initiation (p 0.018). A total of 14 (43.75%) PsA patients had PPF. CD15 infiltrate (410.68 [SD 477.63] cells/mm2) was associated with PPF (p 0.008) in PsA patients. Sixteen (55.17%) patients with UA had PPF, and 13 (44.82%) had LN + . In this group, synovial CD68 + macrophages cells density was negatively correlated with DAS28-CRP (r = - 0.346, p 0.042). CONCLUSIONS: The presence of LN + and higher CD15 + polymorphonuclear cells infiltrate was associated with PPF in RA and PsA, respectively. No associations were found for UA. These findings suggest a great heterogeneity of the ST features and its pathogenic implications in the subtypes of inflammatory arthritis.

Neutrófilos, trampas extracelulares de neutrófilos y artritis reumatoide: una revisión actualizada para clínicos / Neutrophils, neutrophil extracellular traps, and rheumatoid arthritis: An updated review for clinicians

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the presence of autoantibodies. Research on the pathogenic mechanisms involved in systemic autoimmune diseases has largely focused on the involvement of the adaptive immune system with dysregulated responses of T and B cells. However, in recent years, there is increasing evidence of the significant role played by the innate immune system, particularly neutrophils, in these diseases, particularly in RA. Neutrophil extracellular traps (NETs) are extracellular structures composed of remodeled and concentrated chromatin with DNA, histones, and neutrophil proteins, and were first described in 2004. It has been studied that NETs may play a pathogenic role in RA and could be a source of autoantigens, increasing the immune response in the form of autoantibodies in this disease. The possible role of NETs and other markers of neutrophil activation as biomarkers of activity in RA and other immune-mediated diseases has also been studied.This article reviews the role of NETs in RA. It discusses the role of neutrophils and the latest advances in NETs, especially their involvement in autoimmune phenomena in RA. Finally, a literature review is conducted on the determination of NETs in peripheral blood and their relationship as a biomarker of RA activity, as well as their potential role in disease monitoring.(AU)

La artritis reumatoide (AR) es una enfermedad autoinmune sistémica caracterizada por la presencia de autoanticuerpos. Las investigaciones sobre los mecanismos patogénicos implicados en las enfermedades autoinmunes sistémicas se centran en gran medida en la participación del sistema inmunitario adaptativo con las respuestas desreguladas de las células T y B. Sin embargo, en los últimos años, ha aumentado la evidencia del importante papel que juega el sistema inmunitario innato, en particular los neutrófilos, en estas enfermedades, particularmente en la AR. Las trampas extracelulares de neutrófilos (NET) son estructuras extracelulares compuestas por cromatina remodelada y concentrada con ADN, histonas y proteínas de los neutrófilos y son un mecanismo de acción de los neutrófilos que se describió por primera vez en 2004. Se ha estudiado que pueden desempeñar un papel patogénico en la AR y podrían ser fuente de autoantígenos e incrementar la respuesta inmunológica en forma de autoanticuerpos en esta enfermedad. También se ha estudiado el posible papel de las NET y otros marcadores de activación neutrofílica como biomarcadores de actividad en la AR y otras enfermedades inmunomediadas.En el presente artículo se revisa el papel de las NET en la AR. Se revisa el papel del neutrófilo y los últimos avances en NET, especialmente en su participación en los fenómenos de autoinmunidad en la AR. Por último, se hace una revisión de la literatura sobre la determinación de NET en sangre periférica y su relación como biomarcador de actividad de la AR y su posible papel para monitorizar la enfermedad.(AU)

Neutrophils, neutrophil extracellular traps, and rheumatoid arthritis: An updated review for clinicians.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the presence of autoantibodies. Research on the pathogenic mechanisms involved in systemic autoimmune diseases has largely focused on the involvement of the adaptive immune system with dysregulated responses of T and B cells. However, in recent years, there is increasing evidence of the significant role played by the innate immune system, particularly neutrophils, in these diseases, particularly in RA. Neutrophil extracellular traps (NETs) are extracellular structures composed of remodeled and concentrated chromatin with DNA, histones, and neutrophil proteins, and were first described in 2004. It has been studied that NETs may play a pathogenic role in RA and could be a source of autoantigens, increasing the immune response in the form of autoantibodies in this disease. The possible role of NETs and other markers of neutrophil activation as biomarkers of activity in RA and other immune-mediated diseases has also been studied. This article reviews the role of NETs in RA. It discusses the role of neutrophils and the latest advances in NETs, especially their involvement in autoimmune phenomena in RA. Finally, a literature review is conducted on the determination of NETs in peripheral blood and their relationship as a biomarker of RA activity, as well as their potential role in disease monitoring.

Calprotectin in Patients with Rheumatic Immunomediated Adverse Effects Induced by Checkpoints Inhibitors.

BACKGROUND: this is an exploratory study to evaluate calprotectin serum levels in patients with rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) treatment. METHODS: this is a retrospective observational study including patients with irAEs rheumatic syndromes. We compared the calprotectin levels to those in a control group of patients with RA and with a control group of healthy individuals. Additionally, we included a control group of patients treated with ICI but without irAEs to check calprotectin levels. We also analysed the performance of calprotectin for the identification of active rheumatic disease using receiver operating characteristic curves (ROC). RESULTS: 18 patients with rheumatic irAEs were compared to a control group of 128 RA patients and another group of 29 healthy donors. The mean calprotectin level in the irAE group was 5.15 µg/mL, which was higher than the levels in both the RA group (3.19 µg/mL) and the healthy group (3.81 µg/mL) (cut-off 2 µg/mL). Additionally, 8 oncology patients without irAEs were included. In this group, calprotectin levels were similar to those of the healthy controls. In patients with active inflammation, the calprotectin levels in the irAE group were significantly higher (8.43 µg/mL) compared to the RA group (3.94 µg/mL). ROC curve analysis showed that calprotectin had a very good discriminatory capacity to identify inflammatory activity in patients with rheumatic irAEs (AUC of 0.864). CONCLUSIONS: the results suggest that calprotectin may serve as a marker of inflammatory activity in patients with rheumatic irAEs induced by treatment with ICIs.

Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus.

BACKGROUND: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). OBJECTIVES: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. METHODS: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. RESULTS: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. CONCLUSIONS: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.

Importancia de los títulos de anticuerpos antifosfolípidos no criterio entre pacientes con síndrome antifosfolípido primario y pacientes con lupus eritematoso sistémico / Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus

Antecedentes: Hay un interés creciente en el estudio de los anticuerpos antifosfolípidos (aPL) no criterio, incluyendo anticuerpos contra el dominio 1 de la B2 glicoproteína 1 (anti-D1 B2GP1) y anticuerpos antifosfatidilserina/protrombina (PS/PT). Objetivos: Nuestro objetivo fue analizar un panel de aPL convencionales y no criterio en una cohorte de pacientes con lupus eritematoso sistémico (LES) y síndrome antifosfolípido primario (SAF), para describir si hay diferencias en los títulos de aPL entre los grupos, y evaluar asociaciones clínicas incluyendo el riesgo de eventos recurrentes con aPL novedosos. Metodología: Estudio observacional que evaluó los anticuerpos anti-D1 B2GP1 y anti-PS/PT de manera basal. Los anticuerpos anti-D1 B2GP1 se evaluaron a través de inmunoanálisis por quimioluminiscencia. Los anticuerpos anti-PS/PT, anticardiolipinas (aCL) y anti-B2GP1 fueron evaluados por técnicas de ELISA. Finalmente, los pacientes fueron seguidos en el tiempo para identificar nuevos eventos trombóticos. Resultados: Se incluyeron 133 pacientes con LES y 23 pacientes con SAF primario. Las principales manifestaciones de SAF fueron TVP (27%), morbilidad obstétrica (22%) y trombosis arterial (10,1%). Los títulos de anticuerpos anti-PS/PT IgM fueron 46,5 (20,6-127) vs. 21,9 (11,2-39,2) U/ml, p<0,001, en pacientes con SAF primario vs. LES con SAF secundario, respectivamente. Los anti-D1 B2GP1, anti-PS/PT IgG e IgM se asociaron con manifestaciones trombóticas y no trombóticas. Durante el seguimiento, los anticuerpos IgG B2GP1 se relacionaron con un riesgo acumulativo significativo de trombosis. Conclusiones: Se encontraron diferencias estadísticamente significativas en títulos séricos de aPL no criterio en pacientes con SAF primario vs. pacientes con LES y SAF secundario. Si los títulos de aPL no criterio son útiles para diferenciar entre SAF primario y SAF secundario, se requieren más análisis en otras poblaciones para poder confirmar si los títulos de aPL no criterio.

Background: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). Objectives: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. Methods: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. Results: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. Conclusions: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.(AU)

Complete disappearance of pulmonary rheumatoid nodules after long term rituximab treatment: case report.

The natural history of pulmonary rheumatoid nodules in rheumatoid arthritis remains uncertain. We present a case of a patient with rheumatoid arthritis with pulmonary rheumatoid nodules diagnosed while receiving etanercept in whom pulmonary nodules resolved completely after 5 years of rituximab treatment. Rituximab has been evaluated in case series of patients with pulmonary rheumatoid nodules, resulting in most cases in no progression or a reduction in the size of the nodules, although the complete resolution is uncommon probably due to the short follow-up period. Complete disappearance of pulmonary rheumatoid nodules may be expected after long-term treatment with rituximab.

From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis.

S100A9/S100A8 (calprotectin), a member of the S100 protein family, has been shown to play a pivotal role in innate immunity activation. Calprotectin plays a critical role in the pathogenesis of rheumatoid arthritis (RA), as it triggers chemotaxis, phagocyte migration and modulation of neutrophils and macrophages. Higher calprotectin levels have been found in synovial fluid, plasma, and serum from RA patients. Recent studies have demonstrated better correlations between serum or plasma calprotectin and composite inflammatory disease activity indexes than c-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR). Calprotectin serum levels decreased after treatment, independently of the DMARD type or strategy. Calprotectin has shown the strongest correlations with other sensitive techniques to detect inflammation, such as ultrasound. Calprotectin independently predicts radiographic progression. However, its value as a biomarker of treatment response and flare after tapering is unclear. This update reviews the current understanding of calprotectin in RA and discusses possible applications as a biomarker in clinical practice.

Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors.

Objectives: To analyse the accuracy of plasma calprotectin in patients with rheumatoid arthritis (RA) receiving monoclonal antibodies against IL-6 receptors (anti-rIL-6) or JAK inhibitors (JAKis) in detecting ultrasound (US) synovitis and compare it with acute phase reactants [high-sensitivity C-reactive protein (hs-CRP) and ESR]. Methods: An observational cross-sectional study of RA patients receiving anti-rIL-6 (tocilizumab or sarilumab) or JAKi, (baricitinib or tofacitinib) was made. Plasma calprotectin for the diagnosis of US synovitis [synovial hypertrophy grade (SH) ⩾ 2 plus power Doppler signal (PD) ⩾ 1] was analysed using receiver operating characteristic curves (ROCs). The performance of ESR and hs-CRP was also studied. The three ROC curves were compared to determine which had the highest discriminatory power. Associations between plasma calprotectin and US scores were made using correlation analysis. Results: Sixty-three RA patients were included. Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 µg/ml; p = 0.0003). A moderate correlation between calprotectin and all US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495) was found. The discriminatory capacity of plasma calprotectin showed an AUC of 0.795 (95% CI: 0.687-0.904). The AUC of hs-CRP and ESR was 0.721 and 0.564, respectively. hs-CRP serum levels showed a low positive correlation with the three US scores (Rho < 0.40). After analysis according to the drugs administered, the correlation disappeared in patients receiving anti-rIL-6. Conclusion: Plasma calprotectin may be a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.

Imaging Findings in Patients with Immune Checkpoint Inhibitor-Induced Arthritis.

Immune checkpoint inhibitor (ICI)-induced arthritis is an increasingly recognized adverse event in patients with oncologic disease during immunotherapy. Four patterns are well described, including rheumatoid arthritis (RA)-like, polymyalgia rheumatica (PMR)-like, psoriatic arthritis (PsA)-like, and oligo-monoarthritis, among others. Despite better clinical recognition of these syndromes, information about the main imaging findings is limited. METHODS: We conducted a retrospective observational study including all adult patients referred to the Rheumatology Department of a single-center due to ICI-induced arthritis who underwent imaging studies [ultrasound (US), magnetic resonance imaging (MRI), and 18F-FDG PET/CT)] between January 2017 and January 2022. RESULTS: Nineteen patients with ICI-induced arthritis with at least one diagnostic imaging assessment were identified (15 US, 4 MRI, 2 18F-FDG PET/CT). Most patients were male (84.2%), with a median age at inclusion of 73 years. The main underlying diagnoses for ICI treatment were melanoma in five cases. The distribution of ICI-induced arthritis was as follows: PMR-like (5, 26.2%), RA-like (4, 21.1%), PsA-like (4, 21.1%), and others (6, 31.6%). All RA-like patients had US findings indistinguishable from conventional RA patients. In addition, 3/5 (60%) of PMR-like patients had significant involvement of the hands and wrists. Abnormal findings on MRI or PET-CT were reported by clinical symptoms. No erosions or myofascitis were seen. CONCLUSIONS: ICI-induced arthritis patients present inflammatory patterns on imaging studies similar to conventional inflammatory arthropathies, and therefore these syndromes should be followed carefully and treated according to these findings.

Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Immune-Related Adverse Events Induced by Checkpoint Inhibitors. A Multicenter Study.

Objectives: To describe different clinical patterns of rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI) and their rheumatic and oncologic outcomes. Methods: We classified clinical syndromes according to five different categories: non-inflammatory arthralgias (NIA), rheumatoid arthritis (RA)-like, psoriatic arthritis (PsA)-like, polymyalgia rheumatica (PMR)-like, and a miscellaneous group of patients with other syndromes. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response, and outcome. Results: We included 73 patients (64% male) with a mean age of 66.1 ± 11.6 years. Main underlying diagnosis was lung carcinoma in 29 (39%) patients, melanoma in 20 (27%), and renal-urothelial cancer in 11 (15%). Main ICI included Pembrolizumab in 24 (32%), Nivolumab 17 (23%), and Atezolizumab 7 (9 %). Seventeen out of seventy-three patients had an underlying rheumatic disease before ICI treatment. Fourteen patients developed other irAEs before or simultaneously with rheumatic syndromes. Main rheumatic irAEs included: RA-like in 31 (42.4%), NIA in 19 (26.0%), PMR-like in 10 (13.7%), and PsA-like in 5 (6.8%), among others. Median time from ICI to irAEs was 5 months (IQR 3-9). Those patients who received combined therapy, had a trend for an earlier presentation than those who received monotherapy (4.3 months IQR 1.85-17 vs. 6 months IQR 3-9.25, p = NS). Mean follow-up time was 14.0 ± 10.8 (SD, months). At the last visit, 47 % were taking glucocorticoids and 11% DMARD therapy. At the last visit, 13 (17.8%) patients remained with persistent arthritis, 19 (26%) had intermittent flares, and 39 (53.4%) had a self-limited pattern. Only in 15.1% of patients ICI therapy was discontinued. Conclusions: We described different patterns according to treatment and irAEs. Combined ICI therapy had an earlier onset of symptoms. Patients who presented as RA-like, had a higher risk of persistent arthritis. After a mean follow-up of more than 1 year, one-fifth of the patients remained with persistent arthritis and 11% required DMARD therapy.

Analytical and clinical evaluation of DiaSorin Liaison® Calprotectin fecal assay adapted for serum samples.

BACKGROUND: Calprotectin is a calcium-binding protein that can be measured in serum, plasma, and feces. Increased serum and plasma calprotectin concentrations have been found in chronic inflammatory rheumatic disorders. An analytical and clinical evaluation of the DiaSorin Liaison® fecal Calprotectin assay using LIAISON® XL was performed. METHODS: The protocol included an analytical and clinical evaluation in which imprecision, the linearity of dilution, differences between serum and plasma samples and method comparison with CalproLab™ ELISA kit were assessed. Serum calprotectin concentrations in active (n = 26) and remission (n = 23) rheumatoid arthritis (RA) patients were compared. RESULTS: The intra-day and inter-day analytical imprecision CVs ranged from 2.9% to 4.0% and 2.7% to 10.4%, respectively. Correlation between measured and expected values was high (R > 0.99), indicating good linearity. The Wilcoxon signed-rank test showed that serum and plasma matched samples presented statistically significant differences (p < 0.001) being the highest concentrations of calprotectin observed in serum samples. Deming regression equation was as follows: Diasorin calprotectin (µg/ml) = -0.32 (95% CI: -0.65 - -0.05) +1.58 (95% CI: 1.42-1.79).* Calprolab calprotectin (µg/ml). Significantly higher serum calprotectin levels were found in RA patients with active disease when compared to patients with low disease activity or in clinical remission (mean ± SD) [(3.35 µg/ml ± 1.55) vs. (1.63 µg/ml ± 0.52), p < 0.001] and these levels correlated well with all disease activity indices. CONCLUSIONS: The DiaSorin Liaison® fecal Calprotectin assay adapted for serum samples showed adequate technical performances and the clinical performances were similar to other assays.

High Sensitivity C Reactive Protein in Patients with Rheumatoid Arthritis Treated with Antibodies against IL-6 or Jak Inhibitors: A Clinical and Ultrasonographic Study.

BACKGROUND: We examined whether high-sensitivity CRP (hsCRP) reflected the inflammatory disease status evaluated by clinical and ultrasound (US) parameters in RA patients receiving IL-6 receptor antibodies (anti-IL-6R) or JAK inhibitors (JAKi). METHODS: We conducted a cross-sectional study of patients with established RA receiving anti-IL-6R (tocilizumab, sarilumab) or JAKi (tofacitinib, baricitinib). Serum hsCRP and US synovitis in both hands were measured. Associations between hsCRP and clinical inflammatory activity were evaluated using composite activity indices. The association between hsCRP and US synovitis was analyzed. RESULTS: 63 (92% female) patients (42 anti- IL-6R and 21 JAKi) were included, and the median disease duration was 14.4 (0.2-37.5) years. Most patients were in remission or had low levels of disease. Overall hsCRP values were very low, and significantly lower in anti-IL-6R patients (median 0.04 mg/dL vs. 0.16 mg/dL). Anti-IL-6R (82.4%) patients and 48% of JAKi patients had very low hsCRP levels (≤0.1 mg/dL) (p = 0.002). In the anti-IL-6R group, hsCRP did not correlate with the composite activity index or US synovitis. In the JAKi group, hsCRP moderately correlated with US parameters (r = 0.5) but not clinical disease activity, and hsCRP levels were higher in patients with US synovitis (0.02 vs. 0.42 mg/dL) (p = 0.001). CONCLUSION: In anti-IL-6R RA-treated patients, hsCRP does not reflect the inflammatory disease state, but in those treated with JAKi, hsCRP was associated with US synovitis.

Proliferative synovitis, an ultrasound pattern associated with ACPA-positive patients and erosive disease in rheumatoid arthritis.

OBJECTIVES: To analyse ultrasound (US) differences between rheumatoid arthritis (RA) patients according to autoantibody status and characterise the clinical and radiological features associated with the US pattern of seropositive patients. METHODS: We collected demographic and clinical data and bilateral hand US images of RA patients. We defined an extreme proliferative US pattern, encompassing synovial hypertrophy grade II-III with Power Doppler signal, which we called US proliferative synovitis (US PS). To better characterise US PS, MRI of the dominant hand and immunostaining of synovial biopsies were made in subgroups of 42 and 23 patients, respectively. RESULTS: We included 205 RA patients (84.8% seropositive). No significant differences in disease activity were found according to autoantibody status. US PS was found in 55.5% of seropositive and 16.1% of seronegative patients (p=0.0001). In the multivariate analysis, erosions [OR 4.90 95% CI (2.17-11.07), p=0.0001] and ACPA [OR 3.5 95% CI (1.39-10.7), p=0.009] but not RF status [OR 0.74 95% CI (0.31-1.71), p=0.483] were independently associated with US PS. After a mean follow-up of 46 months, US PS was independently associated with changes in therapy (OR 2.63, 95% CI 1.20-5.77, p=0.016). Ninety-four per cent of joints with US PS had RAMRIS synovitis sub-index grade 2-3. US PS was significantly associated with higher synovial vessel density (p=0.042). CONCLUSIONS: In RA patients, US PS was associated with ACPA status, erosive disease and an enhanced need to change disease-modifying anti-rheumatic drug therapy in the long-term. At synovial level, this US pattern was characterised by higher vessel density.

Diagnosis and treatment of articular manifestations of systemic lupus erythematosus / Diagnóstico y tratamiento de las manifestaciones articulares del lupus eritematoso sistémico

ABSTRACT Articular involvement in Systemic Lupus Erythematosus (SLE) is well recognized as one of the most common manifestations of the disease. This article reviews the recent knowledge of the clinical manifestations, diagnostic techniques and therapies used for the treatment of joint involvement in SLE. The degree of articular involvement is characterized by widespread heterogeneity in terms of clinical presentation and severity. It may range from minor arthralgia without erosions or deformity to erosive arthropathy and severe functional disability. Inflammatory musculoskeletal manifestations are described as a major cause of pain impacting daily activities and as a major determinant of quality-of-life impairment. Thus, physicians must be aware of articular involvement in SLE. Lupus arthritis diagnosis may be challenging, due to the frequently mild synovitis. The introduction of new more sensitive imaging techniques, such as ultrasound, and MRI have contributed significantly to improving the diagnosis of osteoarticular involvement in SLE. There are several treatment options for the management of joint manifestations in patients with SLE. The choice of treatment will depend on the type and pattern of joint involvement, its severity, and the characteristics of the patient.

RESUMEN El compromiso articular en lupus eritematoso sistémico (LES) es bien reconocido como una de las manifestaciones más comunes de la enfermedad. En el presente artículo se revisa la evidencia reciente sobre las manifestaciones clínicas, las técnicas de diagnóstico y los tratamientos utilizados para tratar el compromiso articular en el LES. El grado de compromiso articular se caracteriza por la amplia heterogeneidad en su presentación clínica y su gravedad. Puede variar desde artralgia leve sin erosiones o deformidad, hasta una artropatía erosiva y discapacidad funcional. Se describen las manifestaciones inflamatorias musculoesqueléticas como la principal causa de dolor que afecta las actividades de la vida cotidiana y como uno de los principales factores determinantes del deterioro de la calidad de vida. Por lo tanto, los médicos deben estar conscientes del compromiso articular en LES. El diagnóstico de la artritis lúpica puede ser difícil debido a la sinovitis, usualmente leve. El advenimiento de nuevas técnicas de imágenes más sensibles, como la ecografía y la resonancia magnética, ha contribuido significativamente a mejorar el diagnóstico del compromiso osteoarticular en LES. Existen varias opciones de tratamiento para las manifestaciones articulares en pacientes con LES. La opción de tratamiento dependerá del tipo y del patrón del compromiso articular, así como de las características del paciente.

Palindromic Rheumatism: Just a Pre-rheumatoid Stage or Something Else?

Palindromic rheumatism (PR), a unique clinical entity, has a characteristic clinical presentation with a relapsing/remitting course. It is established that most patients with PR evolve to chronic disease, of which rheumatoid arthritis (RA) is by far the most common. The relationship between PR and RA is unclear, with similarities and differences between the two, and not all patients evolve to RA in the long-term. Therefore, PR is clearly a pre-RA stage for most, but not all, patients. Autoimmunity plays a substantial role in PR, with the same characteristic autoantibody profile observed in RA, although with some differences in the immune response repertoire. Autoinflammation may also be relevant in some cases of PR. Prognostic factors for RA progression are identified but their exact predictive value is not clear. There are several unmet needs in PR, such as the diagnostic criteria and clinical case definition, the pathogenic mechanisms involved in the unusual clinical course, and the evolution to RA, and our understanding of the therapeutic strategy that could best avoid progression to persistent and potentially destructive arthritis.