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Background Despite an increasing number of targeted and biological disease-modifying anti-rheumatic drugs (ts or bDMARDs), a significant number of Rheumatoid Arthritis (RA) patients are refractory to multiple lines of treatments. The definition of Difficult-to-treat (D2T) RA patients has been proposed to harmonize research on this condition. While data on D2T in established RA are emerging, this is the first study to specifically address the evolution from early disease (ERA) to D2T-RA. To identify early clinical, laboratory, and radiographic predictors of progression from early rheumatoid arthritis to difficult-to-treat RA over a five-year follow-up. Methods This was a retrospective monocentric cohort study of DMARD-naïve ERA patients (symptom duration ≤ 12 months), enrolled between 2010 and 2019. Patients were followed for 5 years with data collection at baseline, 6, 12, 36, and 60 months. The primary outcome was the development of D2T-RA, defined according to EULAR 2021 criteria. Baseline analyzed variables included clinical features, serology, radiographic damage, disease activity scores, patient-reported outcomes (PROs) and demographic features. Associations between baseline variables and D2T status were evaluated using univariate and multivariate logistic regression analyses. Results We included 391 ERA patients [M/F 109/282, median age 48.2 years IQR (21.26)]. After 5 years, forty-one patients (10.5%) matched the D2T definition. A higher baseline radiographic damage, seropositivity, and baseline disease activity characterized these patients. Only radiographic damage was confirmed as an independent factor for progression to D2T-RA in a multivariate analysis [OR = 2.38 CI (1.09–5.54); p  = 0.03]. During the follow-up, disease activity was consistently higher in the D2T group. D2T patients were exposed to a higher dose of glucocorticoids and more commonly suffered from infections and osteoporosis. Conclusions Baseline radiographic damage, seropositivity, and high disease activity represent the major risk factors for the evolution from ERA to D2T-RA. Disease activity indices were consistently higher in D2T patients all along the five-year follow-up. In addition, D2T patients received higher GC doses and more commonly developed disease and treatment-related comorbidities.

Objective Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). Methods 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0–3 scale with 7 levels. Results A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [ r  = 0.44 (0.27 − 0.56); p  < 0.0001]. CD68 correlated with C-Reactive Protein (CRP), DAS28, SDAI and CDAI. Fibrinoid Necrosis score correlated with CRP and DAS28. Patients were then categorized as CD68Necrosis HIGH (CD68 + Necrosis ≥ 3) and CD68Necrosis LOW (CD68 + Necrosis < 3). CD68Necrosis HIGH exhibited higher pre-treatment disease activity [5.48 (1.6) versus 4.8 (1.7); p  = 0.03] and a greater fall in DAS28 [1.99 (2.06) versus 1.1 (2.27), p  = 0.03], SDAI [21.45 (IQR 23.3) versus 11.65 (IQR 17.5); p  = 0.003] and CDAI [16 [14.9] versus 10.5 (20.1), p  = 0.04]. CD68Necrosis HIGH patients had a higher EULAR Moderate/Good Response rate. CD68Necrosis score was incorporated into a probability matrix model together with clinical features (SJC44 and DAS28) to predict achieving a Moderate/Good EULAR Response Criteria at 3 months with a good performance (AUC 0.724). Conclusion FN and CD68 + in ERA synovial biopsies identify patients with higher disease activity and predict a better treatment response at three months. A model including synovial CD68 and fibrinoid necrosis with baseline clinical features predicts EULAR response at 3 months.

Limited evidences are available on biomarkers to recognize Systemic Lupus erythematosus (SLE) patients at risk to develop erosive arthritis. Anti-citrullinated peptide antibodies (ACPA) have been widely investigated and identified in up to 50% of X-ray detected erosive arthritis; conversely, few studies evaluated anti-carbamylated proteins antibodies (anti-CarP). Here, we considered the application of machine learning models to identify relevant factors in the development of ultrasonography (US)-detected erosive damage in a large cohort of SLE patients with joint involvement. We enrolled consecutive SLE patients with arthritis/arthralgia. All patients underwent joint (DAS28, STR) and laboratory assessment (detection of ACPA, anti-CarP, Rheumatoid Factor, SLE-related antibodies). The bone surfaces of metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered with a dichotomous value (0/1), obtaining a total score (0-20). Concerning machine learning techniques, we applied and compared Logistic Regression and Decision Trees in conjunction with the feature selection Forward Wrapper method. We enrolled 120 SLE patients [M/F 8/112, median age 47.0 years (IQR 15.0); median disease duration 120.0 months (IQR 156.0)], 73.3% of them referring at least one episode of arthritis. Erosive damage was identified in 25.8% of patients (mean±SD 0.7±1.6), all of them with clinically evident arthritis. We applied Logistic Regression in conjunction with the Forward Wrapper method, obtaining an AUC value of 0.806±0.02. As a result of the learning procedure, we evaluated the relevance of the different factors: this value was higher than 35% for ACPA and anti-CarP. The application of Machine Learning Models allowed to identify factors associated with US-detected erosive bone damage in a large SLE cohort and their relevance in determining this phenotype. Although the scope of this study is limited by the small sample size and its cross-sectional nature, the results suggest the relevance of ACPA and anti-CarP antibodies in the development of erosive damage as also pointed out in other studies.

Background The application of more sensitive imaging techniques, such as ultrasonography (US), changed the concept of non-erosive arthritis in systemic lupus erythematosus (SLE), underlining the need for biomarkers to identify patients developing the erosive phenotype. Anti-citrullinated peptide antibodies (ACPA), associated with erosions in inflammatory arthritis, have been identified in about 50% of patients with SLE with erosive arthritis. More recently, anti-carbamylated proteins antibodies (anti-CarP) have been associated with erosive damage in rheumatoid arthritis. We aimed to assess the association between anti-CarP and erosive damage in a large SLE cohort with joint involvement. Methods We evaluated 152 patients (male/female patients 11/141; median age 46 years, IQR 16; median disease duration 108 months, IQR 168). All patients underwent blood draw to detect rheumatoid factor (RF) and ACPA (commercial enzyme-linked immunosorbent assay (ELISA) kit), and anti-CarP (“home-made” ELISA, cutoff 340 aU/mL). The bone surfaces of the metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered as a dichotomous value (0/1), obtaining a total score (0–20). Results The prevalence of anti-CarP was 28.3%, similar to RF (27.6%) and significantly higher than ACPA (11.2%, p  = 0.003). Erosive arthritis was identified in 25.6% of patients: this phenotype was significantly associated with anti-CarP ( p  = 0.004). Significant correlation between anti-CarP titer and US erosive score was observed ( r  = 0.2, p  = 0.01). Conclusions Significant association was identified between anti-CarP and erosive damage in SLE-related arthritis, in terms of frequency and severity, suggesting that these antibodies can represent a biomarker of severity in patients with SLE with joint involvement.

Objective. The role of T cells in the pathogenesis of systemic lupus erythematosus (SLE) has recently gained attention. Costimulatory molecules are membrane proteins strictly associated with T-cell receptor (TCR), acting by activating or inhibiting T cells and antigen-presenting cells (APC) through direct and reverse signaling, thus becoming responsible for the development of effector T cells or regulatory T cells. The primary objective of the present case–control study was to evaluate the cell membrane expression of CD137 on T cells and the serum concentration of CD137 (sCD137) in a SLE cohort. Materials. We enrolled SLE patients and sex/age-matched healthy subjects (HS). Disease activity was assessed by SLEDAI-2K. By application of flow cytometry, we evaluated the expression of CD137 on CD4+ and CD8+ lymphocytes. ELISA test was performed to evaluate serum levels of sCD137. Results. Twenty-one SLE patients (M/F 1/20; median age 48 years (IQR 17); median disease duration 144 months (IQR 204)) were evaluated. SLE patients showed %CD3+CD137+ cells significantly higher compared to HS (median 5.32 (IQR 6.11) versus 3.3 (IQR 1.8), p=0.001). In SLE patients, %CD4+CD137+ cells positively correlated with SLEDAI-2K (p=0.0082, r = 0.58, CI (0.15–0.82); indeed, %CD4+CD137+ cells were significantly lower in SLE patients with a remission status compared to those not reaching this condition (median 1.07 (IQR 0.91) versus 1.58 (IQR 2.42), p=0.013). Accordingly, sCD137 levels were significantly lower in remission status (31.30 pg/mL (IQR 102.2 versus median 122.8 pg/mL (IQR 536); p=0.03) and correlated with %CD4+CD137+ cells (p=0.012, r = 0.60, CI (0.15–0.84)). Conclusion. Our results suggest a possible involvement of CD137-CD137L axis in SLE pathogenesis, as demonstrated by higher expression of CD137 on CD4+ cells in SLE compared with HS. Furthermore, the positive correlation between SLEDAI-2K and membrane CD137 expression on CD4+ cells, as well as soluble CD137, indicates a possible use as biomarkers for disease activity.

The introduction of the so-called immune checkpoint inhibitors (ICIs) substantially changed the history of cancer therapy. On the other hand, they can induce the development of rheumatic immune-related adverse events (Rh-irAEs). In the scenario of a joint oncology/rheumatology outpatient clinic, we conducted a single-centre descriptive study to define from a laboratory, clinical and therapeutic point of view, rheumatic conditions developed during anti-PD1 treatment. The study included 32 patients (M/F 16/16, median age 69, IQR 16.5). According to the international classification criteria, eight patients could be classified as affected by Rheumatoid Arthritis, one by Psoriatic Arthritis, six by Polymyalgia Rheumatica, five by systemic connective tissue diseases (two systemic lupus erythematosus, two Sjögren’s syndrome, one undifferentiated connective tissue disease). The remaining patients were diagnosed as having undifferentiated arthritis or inflammatory arthralgia. The median interval between ICIs starting and the onset of symptoms was 14 weeks (IQR 19.75). Moving to treatment, the longitudinal observation revealed that all RA, PsA and CTD patients required the introduction of treatment with DMARDs. In conclusion, the growing use of ICIs in a real-life setting confirmed the possible development of different rheumatological conditions, further emphasising the need for shared oncology/rheumatology management.

Autophagy is a homeostatic process responsible for the self-digestion of intracellular components and antimicrobial defense by inducing the degradation of pathogens into autophagolysosomes. Recent findings suggest an involvement of this process in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the role of autophagy in the immunological mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis remains largely unexplored. This study reveals the presence of autophagy defects in peripheral immune cells from COVID-19 patients. The impairment of the autophagy process resulted in a higher percentage of lymphocytes undergoing apoptosis in COVID-19 patients. Moreover, the inverse correlation between autophagy markers levels and peripheral lymphocyte counts in COVID-19 patients confirms how a defect in autophagy might contribute to lymphopenia, causing a reduction in the activation of viral defense. These results provided intriguing data that could help in understanding the cellular underlying mechanisms in COVID-19 infection, especially in severe forms.

Background/purposeImmune checkpoint inhibitor-induced arthritis (ICI-IA) is the most common rheumatic immune-related adverse event (irAEs). Its pathogenesis remains unknown. Ultrasound (US)-guided synovial biopsy (USGSB) has been proven to be a safe and reliable procedure in rheumatoid arthritis (RA), enlarging the understanding of synovitis in RA. To the best of our knowledge, no studies have analyzed the histology of ICI-induced arthritis. This study aimed to describe ICI-IA from clinical presentation to histology.Materials and methodsPatients who developed inflammatory arthritis while under treatment by ICIs were enrolled. A US assessment of 38 joints [shoulders, elbows, knees, wrists, metacarpophalangeal joints (MCPs), proximal interphalangeal joints (PIPs), and metatarsophalangeal joints (MTPs)] was systematically performed for inflammatory assessment and joint selection before synovial biopsy. Histopathological analyses consisted of semiquantitative scores for histological parameters (synovial hyperplasia, fibrinoid necrosis, hypervascularization, and inflammatory infiltrate) and immunohistochemistry staining (CD3, CD20, CD138, and CD68). As a control group, we enrolled age- and sex-matched untreated early RA (ERA) patients with synovial tissue available.ResultsA total of 13 patients were included [men/women (10/3), with a median age of 65 years (interquartile range: IQR: 14.5)]. Overall, seven patients suffered from polyarthritis (53.8%), and five (38.4%) suffered from oligoarthritis. The US pre-biopsy evaluation detected synovitis in 23.4% of joints; the most involved was the knee, followed by wrist, elbow, MCP2, MCP3, and MTP 2–5. Samples for synovial tissue analysis were primarily obtained from the knee (69.2%). The histology of ICI-induced arthritis demonstrated a synovial inflammation similar to that found in ERA. ICI-IA and ERA show similar clinical and histological characteristics.ConclusionClinically, ICI-IA manifested as oligoarthritis and polyarthritis, similar to RA. Synovial histology in ICI-induced arthritis is indistinguishable from RA, suggesting common pathogenic mechanisms. Further transcriptomics analyses are ongoing to better describe this new arthritis condition.

ObjectiveThe assessment of disease activity in patients with Systemic Lupus Erythematosus (SLE) represents an essential need for clinical practice and clinical trials. Nevertheless, the validation of a sensitive and reproducible instrument remains a challenge for the rheumatologist due to SLE heterogeneity. SLE-DAS (SLE Disease Activity Score), a recently proposed index, demonstrated higher sensitivity to change in comparison to SLEDAI-2k. However, few studies have tested its performance in the assessment of treatment efficacy. Thus, we aimed at assessing the efficacy of subcutaneous (sc) belimumab (BLM) by SLE-DAS in a monocentric SLE cohort. In particular, we evaluated the achievement of remission according to SLE-DAS and DORIS definition. Secondly, we investigated the construct validity of SLE-DAS in comparison with SLEDAI-2k. MethodsWe evaluated SLE patients treated with sc BLM from March 2019. Disease activity has been assessed by SLEDAI-2k, SLE-DAS and PGA (Physician Global Assessment) in all the established time-points [baseline (T0), after 1 (T1), 3 (T3), 6 (T6) and 12 (T12) months]. Furthermore, we applied and compared the achievement of remission according to SLE-DAS values (SLE-DAS ≤2.08 + PDN ≤5mg/daily) and DORIS definition (clinical SLEDAI-2k=0 + PGA<0.5 + antimalarials treatment, PDN≤5mg/daily, stable immunosuppressive treatment).ResultsWe enrolled 86 patients [M/F 5/81, median age 48 years (IQR 17.5), median disease duration 166 months (IQR 216)]. At baseline, median values of SLEDA-2k and SLE-DAS were 6 (IQR 4) and 5.77 (IQR 4.33), respectively, and they significantly correlated (r=0.719, CI 95% 0.586–0.815, p<0.0001; figure 1A). Median duration of treatment was 14 months (IQR 20). We found a significant reduction of SLEDAI-2k and SLE-DAS already at T1, maintained in the subsequent time-points (p<0.0001). At T12, a remission state was achieved by 60.4% of patients according to SLE-DAS definition and by 62.3% according to DORIS one (figure 1B). The two definitions of remission have demonstrated an agreement of 84%, with a Cohen’s kappa equal to 0.6.Abstract P60 Figure 1(A) Correlation analysis by Spearman test between SLEDAI-2k and SLE-DAS at baseline (r=0.719, p<0.0001). (B) Stacked column chart for remission states according to SLE-DAS and DORIS definitionsConclusionsIn this study we applied SLE-DAS to assess the efficacy of sc BLM, by analyzing its over-time changes and by comparing its performance with SLEDAI-2k. Indeed, our results suggest the usefulness of this new activity index in a real-life setting.

[This corrects the article DOI: 10.1371/journal.pone.0207926.].