Remission In Rheumatoid Arthritis Research Articles

The biological activity of serum bacterial lipopolysaccharides associates with disease activity and likelihood of achieving remission in patients with rheumatoid arthritis

BackgroundDysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients.MethodsWe measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays.ResultsThe patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, p<0.001) at 12 months. Importantly, baseline LPS bioactivity correlated with disease activity (p=0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months (p=0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation.ConclusionWe describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor.Graphical A graphical summary of the conclusions of the study.

Case of successful use of sarilumab in secondary renal amyloidosis in a patient with rheumatoid arthritis

Clinical observation of the successful use of the interleukin 6 (IL6) inhibitor sarilumab in secondary renal amyloidosis in a patient with active seropositive rheumatoid arthritis, is presented. This complication was confirmed by biopsy of rectum. The presented clinical example demonstrates a fairly rapid, within five years from the onset of the disease, the development of secondary renal amyolidosis with the formation of a persistent nephrotic syndrome that is resistant to therapy with cyclophosphamide and rituximab. Prescription of the IL6 inhibitor tocilizumab contributed to a decrease in the clinical and laboratory activity of the underlying disease, a decrease in the severity of daily proteinuria, but did not allow to achieve the full effect. The use of another IL6 inhibitor – sarilumab, led to a complete regression of nephrotic syndrome with normalization of general urine analysis, biochemical blood tests – total protein, albumin, total cholesterol, against the background of stable clinical and laboratory remission of rheumatoid arthritis.

Validity of Remission Criteria in Rheumatoid Arthritis Compared to Ultrasound-Defined Remission.

Remission is the ultimate purpose of treatment in rheumatoid arthritis (RA). However, even when the most stringent composite scores are used, structural damages can occur; hence, ultrasonography (US) appears to be the best way to assess real remission. This study aimed to investigate the validity of different RA remission scores using US as a reference. An analytic diagnostic study, of 30 RA patients in remission (according to the Disease Activity Score in 28 Joints [DAS28]) and a control group with active RA, was conducted between January and October 2018 at Mongi Slim Hospital in Tunis, Tunisia. Among them, patients in remission were identified according to their Simple Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and the Boolean American College of Rheumatology/European League against Rheumatism activity index (ACR/EULAR) remission scores. The validity of each activity score for remission was calculated by considering the absence of power Doppler (PD) signals as a gold standard. All patients were in remission according to the DAS28, with an average score of 2.03 (1.1-2.6). US examination showed PD signals in 57% of patients. A total of 26 patients were in remission according to the CDAI; a Doppler signal was detected in 58% of those cases. SDAI remission was accomplished in 19 patients, with PD activity in 53% of cases. Of the 14 patients in remission according to the Boolean ACR/EULAR criteria, synovial hyper-vascularisation was found in 64%. Considering true remission as the absence of PD signals, the most sensitive and specific score was the DAS28 (93% and 68%, respectively). Considering remission in RA as the absence of vascularised synovitis, the DAS28 is the most sensitive and most specific score.

Inflammation mediates approximately one quarter of excess relative all-cause mortality in persons with rheumatoid arthritis: the Trøndelag Health Study

Inflammation may contribute to excess mortality in rheumatoid arthritis (RA) patients. We investigated associations to all-cause mortality of the inflammation markers high-sensitivity C-reactive protein (CRP), lactoferrin (neutrophil activation marker), and neopterin (monocyte activation marker). From the population-based Trøndelag Health Study (3rd wave 2006–2008), 316 RA patients and 43,579 controls were included. Lactoferrin and neopterin were quantified in a nested cohort (n = 283 RA patients, n = 3698 controls). Follow-up was until death found by linkage to the Norwegian Cause of Death Registry or 31.12.2018. All-cause mortality was analyzed using Cox regression and Cox regression-based mediation analysis. Having RA (hazard ratio (HR): 1.25, 95%CI: 1.00, 1.56, p = 0.048), and CRP ≥ 3 mg/L (HR: 1.50, 95%CI: 1.41, 1.60, p < 0.001) were associated with all-cause mortality. The overall excess relative mortality risk of having RA was 38%. CRP ≥ 3 mg/L mediated approximately 1/4 of this risk (p < 0.001). In the nested cohort, CRP ≥ 3 mg/L (HR: 1.51, 95%CI: 1.26, 1.80, p < 0.001) and neopterin (HR: 1.17, 95%CI: 1.01, 1.36, p = 0.031) were associated with all-cause mortality. In conclusion, CRP levels ≥ 3 mg/L mediated approximately a quarter of the 38% excess relative all-cause mortality risk associated with RA. Using definitions of RA remission with emphasis both on joint status and the level of general inflammation may help guide the most efficient treatment regimens.

American College of Rheumatology/EULAR Remission Criteria for Rheumatoid Arthritis: 2022 Revision.

In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean- and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the 2 sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. We used data from 4 randomized trials comparing biologic disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared to the original threshold of 1 cm (Boolean1.0). We analyzed agreement between the Boolean- and index-based criteria (Simplified Disease Activity Index [SDAI] and Clinical Disease Activity Index [CDAI]) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire [HAQ] score ≤0.5) and radiographic nonprogression. Data from 2,048 trial participants, 1,101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared to Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. Using the Boolean 2.0 criteria classifies more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardizing predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Does remission in rheumatoid arthritis bring kinesiophobia, quality of life, fatigue, and physical activity closer to normal?

This study aimed to compare kinesiophobia, fatigue, physical activity, and quality of life (QoL) between the patients with rheumatoid arthritis (RA) in remission and a healthy population. The prospective controlled study included 45 female patients (mean age: 54.22±8.2 year; range, 37 to 67 year) with a diagnosis of RA determined to be in remission according to the Disease Activity Score in 28 Joints (DAS28) being ≤2.6 between January 2022 and February 2022. As a control group, 45 female healthy volunteers (mean age: 52.2±8.2 year; range, 34 to 70 year) of similar age were evaluated. The QoL, disease activity, pain, kinesiophobia, fatigue severity, and physical activity were assessed using the Health Assessment Questionnaire, DAS28, Visual Analog Scale, Tampa Scale of Kinesiophobia, Fatigue Severity Scale, and International Physical Activity Questionnaire, respectively. There was no significant difference between the groups in demographic data. A statistically significant difference was found between the groups in terms of pain, C-reactive protein level, fatigue, kinesiophobia, QoL, and total, high, and moderate physical activity scores (p<0.001). Among the RA patients in remission, there was a significant correlation between kinesiophobia and moderate physical activity and QoL, as well as between fatigue and high physical activity (p<0.05). Patient education and multidisciplinary approach strategies should be developed to increase the QoL and physical activity and reduce kinesiophobia in RA patients in remission since there may be a decrease in physical activity due to kinesiophobia, fatigue, and fear of movement in this patient group compared to the healthy population, impairing their QoL.

Association of adiponectin levels with disease activity score, RA factor and ESR in rheumatoid arthritis patients

Introduction: Rheumatoid arthritis is a chronic inflammatory polyarthritis of relatively common occurrence affecting about 1-2% of adult population world-wide and 0.75% of Indian adults. The disease occurs at all ages and affects all ethnic groups. For early diagnosis and progression of rheumatoid arthritis might be useful for to better treatment of the patients. Present study aimed to assessment of adiponectin in newly diagnosed and remission rheumatoid arthritis patients. Materials and Methods: 100 Rheumatoid arthritis patients and 50 healthy volunteers with matching age, gender, and BMI were included in the study. All the subjects' biochemical, disease activity score, RA factor,ESR Rheumatoid Arthritis Patients and serum adiponectin levels were assessed. SPSS and Microsoft Excel Spreadsheets were used to conduct the necessary statistical analysis. Results: The patients with rheumatoid arthritis shown significantly higher levels of fasting blood sugar, postprandial blood sugars ,triglycerides , RA factor, ESR when compared to healthy controls (P=0.001**). Additionally we also discovered to be considerably significantly elevated levels of serum adiponectin (P= 0.001**). Furthermore there was very high significant positive correlation between serum adiponectin and disease activity score, RA factor, ESR.

Association between patient-reported outcomes and impairments in work and activity in patients with rheumatoid arthritis in clinical remission: A retrospective analysis using the IORRA database.

To explore the patient-reported outcomes (PROs) associated with work productivity and activity impairment (WPAI) in patients with rheumatoid arthritis (RA) in clinical remission. We enrolled patients with RA ≥18 years and with a simplified disease activity index ≤3.3 from the Institute of Rheumatology, Rheumatoid Arthritis data set collected in October 2017. The pain-visual analogue scale, patients' global assessment visual analogue scale (VAS), Japanese version of the Healthcare Assessment Questionnaire (J-HAQ) Disability Index, and duration of morning joint stiffness were selected as the PROs. To evaluate work productivity and activity, the WPAI for RA instrument (WPAI-RA) was used. To assess the contribution of each PRO to the WPAI-RA score, an analysis of variance model was constructed. The mean age of the 2614 patients was 62.4 years; 85.1% were female. Median values of the WPAI-RA score were 1.1% for absenteeism, 6.5% for presenteeism, 7.4% for work impairment, and 10.2% for activity impairment. Morning joint stiffness contributed the most to absenteeism (18.0%), while pain-VAS contributed the most to presenteeism (57.4%), work productivity loss (51.1%), and daily activity impairment (53.7%). J-HAQ was the second most contributing factor to presenteeism (17.4%), work productivity loss (16.3%), and daily activity impairment (26.0%). The pain-VAS and J-HAQ highly contributed to WPAI in patients with RA in clinical remission.

Disease activity trajectories for early and established rheumatoid arthritis: Real-world data from a rheumatoid arthritis cohort.

Disease activity status described at fixed time points does not accurately reflect disease course in chronic and relapsing diseases such as rheumatoid arthritis (RA). We described longitudinal disease activity trajectories in early and established RA. Patients with available 28-Joint Disease Activity Score-erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI) over two years were included. Using latent growth curve modelling (LCGM), subgroups of patients following distinct patterns were identified. 1920 patients were included with 34.4% in early RA (< 2 years' disease duration). Three subgroups were identified using DAS28-ESR in early RA: 1) low disease activity to remission (LDA-REM: 19.1%); 2) moderate disease to remission (MD-REM: 54%); 3) high to moderate disease (HD-MD: 26.9%). The HD-MD group had a significantly higher number of comorbidities, biologic and steroid use and lower post-secondary education. Using CDAI, we identified seven subgroups with only 1.9% remission in early RA. In established RA, seven subgroups were identified using either DAS28-ESR or CDAI. Using DAS28-ESR 27.8% with HD showed improvement in disease status (14.2% HD-REM, 10.3% HD-LDA and 3.3% HD-MD) while using CDAI 17.9% showed improvement. Disease course was different in early and established RA. Only 14.2% of established RA reached DAS28-ESR remission compared to 73.1% of early RA. Using CDAI only 1.9% of early RA and none of the established RA achieved remission, likely reflecting the impact of the patient global assessment on this score. Findings also illustrate the impact of sociodemographic characteristics and early treatment on disease course.

Correlation between anti-mutated citrullinated vimentin and bone turnover markers (CTX-1 and P1NP) in patients with rheumatoid arthritis in remission and low-disease activity

IntroductionRheumatoid arthritis is associated with bone loss and the risk of osteoporotic fracture. Bone loss in this disease is mediated by inflammation and autoimmunity. Many studies have shown that anti-citrullinated protein antibody is capable of inducing bone loss through several mechanisms.This study aimed to determine the relationship between autoimmunity, represented by anti-mutated citrullinated vimentin (anti-MCV) in this study, and bone loss, represented by C-terminal cross-linking telopeptide of type I collagen (CTX-1), and N-terminal pro-peptide of type 1 procollagen (P1NP) in this study, in patients with rheumatoid arthritis in remission and low disease activity.Material and methodsThis study enrolled 38 rheumatoid arthritis patients with disease remission and low disease activity in Cipto Mangunkusumo Hospital between August and September 2019. We collected the patients’ demographic data, Disease Activity Score 28 (DAS28), and treatment history. All participants underwent blood work for anti-MCV, CTX-1, and P1NP.ResultsThirty-four of the subjects were women (89.5%), with the mean age of 40 ±7.6 years and the median disease duration of 36 months. Among the subjects, 26 patients (68.4%) were anti-MCV positive. There was no correlation between anti-MCV and CTX-1 levels (r = 0.101, p = 0.274). There was a moderate negative correlation between anti-MCV and P1NP (r = –0.449, p = 0.001). The mean difference of P1NP according to anti-MCV level also showed a significant difference (p = 0.019)ConclusionsThe anti-MCV levels are not directly correlated with CTX-1 levels, indicating heterogeneity in the disease course even after inflammation has ceased. The anti-MCV and P1NP levels are moderately correlated, indicating that bone formation is resumed during the suppression of autoimmunity.

Correlation of serum citrullinated histone H3 levels with disease activity in patients with rheumatoid arthritis.

Serum citrullinated histone H3 (CitH3) levels in humans with rheumatoid arthritis (RA) were examined and the associations between CitH3 levels and disease variables were investigated. Serum CitH3 levels were measured using an enzyme-linked immunosorbent assay in 151 RA patients (69 with highly, 32 with moderately, and 20 with mildly active RA and 30 with RA in remission) and 56 healthy controls. Receiver operating characteristic curve analysis was performed to evaluate the discriminant capacity of CitH3 between highly/moderately active RA and RA in remission/mild activity. Furthermore, machine-learning methods were applied to construct a predictive model. CitH3 concentration was more upregulated in patients with highly and moderately active RA than in those with mild activity and remission. The area under the curve for CitH3 was 0.825 for discriminating between highly and mildly active RA, 0.840 for discriminating between highly active RA and RA in remission, 0.789 for discriminating between moderately and mildly active RA, and 0.829 for discriminating between moderately active RA and RA in remission. The correlation analysis revealed that serum CitH3 levels were positively associated with Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR), ESR, C-reactive protein, rheumatoid factor, and some routine blood parameters (WBC, RDW, PLT, N, and N%), while negatively associated with haemoglobin, lymphocyte percentage, and thyroid-stimulating hormone. Through machine learning, the optimal predictive model was selected and had high performance. CitH3 is significantly associated with disease activity and could serve as a useful candidate biomarker to assess disease activity in patients with RA.

Validation and predictive capacity of a Dutch version of the FLARE-RA questionnaire within the context of a TNFi-tapering trial.

Flare Assessment in Rheumatoid Arthritis (FLARE-RA) is a self-administered tool aiming to capture current or recent flares in rheumatoid arthritis (RA). We aimed to externally validate the FLARE-RA instrument and its existing cutoffs for flare detection within a bDMARD-tapering context in established RA. Data were analyzed from the Tapering Etanercept in Rheumatoid Arthritis (TapERA) trial, which studied the feasibility of tapering etanercept in patients with established RA in sustained remission. The English FLARE-RA was translated and cross-culturally adapted into Dutch, and internal consistency and test-retest reliability were evaluated with Crohnbach's alpha and intraclass correlation coefficient (ICC). Participants completed the FLARE-RA 3-monthly for 12months. Accuracy and optimal cutoffs of FLARE-RA to detect DAS28-defined flares were assessed using area under the receiver operating characteristic curves (AUC). Association of FLARE-RA scores with current and future flares was studied using logistic generalized estimating equations (GEE). The Dutch FLARE-RA showed excellent internal consistency and test-retest reliability (Cronbach's alpha 0.96; ICC 0.96 [95% CI 0.70-1.00]). Discriminatory capacity of FLARE-RA to detect flares was acceptable (AUC 0.77, 0.80, and 0.72 for global, arthritis, and general symptoms subscales, respectively), with an optimal global score cutoff of 4/10. In GEE-models, higher FLARE-RA scores were associated with increased odds of both current and future flares. We successfully translated and cross-culturally adapted the FLARE-RA into a Dutch version and validated its capacity to detect flares in a bDMARD-tapering context in established RA. Finally, higher FLARE-RA scores might indicate an increased risk of future flares.Trial registration: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004631-22/BE , EudraCT number 2012-004,631-22. Key Points • Translation and cross-cultural adaptation of the FLARE-RA resulted in a Dutch version with excellent internal consistency and test-retest reliability. • The FLARE-RA is a valid instrument to detect current OMERACT-defined flares within a bDMARD tapering setting, with an optimal global score cutoff of 4/10. • Higher scores on the FLARE-RA are associated with increased risk of future flares, which could be particularly relevant when considering DMARD tapering.

Case report: Safety and efficacy of adalimumab in treating difficult-to-treat rheumatoid arthritis in a human immunodeficiency virus-positive patient, one year follow-up

Rheumatoid arthritis (RA) is a joint-disabling inflammatory disease associated with the pathology of synovitis. Some patients with RA are difficult to treat, using disease-modifying anti-rheumatic drugs (DMARDs). Biology and targeted synthetic DMARDs (b/tsDMARDs) are options for patients with RA. Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by the human immunodeficiency virus (HIV). Adalimumab is an anti-tumor necrosis factor therapy commonly used in patients with RA. However, there are no reports or related data on patients with RA-HIV/AIDS treated with adalimumab are available. In this report, we described the first successful case of a 60-year-old HIV-positive woman with difficult-to-treat RA treated with ADA after being screened for hepatitis virus, latent tuberculosis (LTBI), and other infections. She contracted HIV from sexual exposure while on adalimumab therapy. As the patient was resistant to first-line DMARDs, she continued adalimumab along with the initiation of highly active antiretroviral therapy (HAART). The patient was treated with adalimumab therapy for a year; her CD4+ lymphocyte count was normal, HIV-1 RNA decreased, and no new infections were triggered. The patient achieved clinical remission of RA. In conclusion, adalimumab is a safe option for patients with RA-HIV and may slow the progression of HIV infection. Furthermore, HAART has the potential to reduce joint pain and fatigue in patients with difficult-to-treat RA.ConclusionsAdalimumab is a safe option for patients with RA-HIV, and may slow down the progression of HIV infection. The HAART therapy has the potential to reduce joint pain and fatigue in patients with difficult-to-treat RA.

Efficacy and safety of progressively reducing biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in persistent remission: a study protocol for a non-inferiority randomized, controlled, single-blind trial

BackgroundTo compare the effects of two biologic disease-modifying antirheumatic drug (bDMARD) administration strategies on the maintenance effect and safety of patients with rheumatoid arthritis (RA) in remission, to analyze the effects of gradual drug reduction and dose maintenance treatment on clinical outcomes in patients who have achieved remission with different types of bDMARDs, to search and screen out people who may benefit from drug reduction strategies, and to provide references for drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.MethodsThe study will be a 24-month non-inferiority randomized, controlled, single-blind trial and is planned to be launched in our hospital from September 2021 to August 2023. Patients will be randomized in a ratio of 2:1 to two groups: maintenance or injection spacing by 50%/gradual reduction of dosage every 3 months up to complete stop. When the patient relapses, return to the last effective dose. If the remission can be maintained, the medication of bDMARDs can be stopped 9 months after enrollment. The primary outcome will be the persistent flare rate.DiscussionOur study may provide a reference for the selection of drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.Trial registrationChinese Clinical Trial Registry ChiCTR2100044751. Registered on 26 March 2021

Assessment of inflammation in patients with rheumatoid arthritis using thermography and machine learning: a fast and automated technique

ObjectivesSensitive detection of joint inflammation in rheumatoid arthritis (RA) is crucial to the success of the treat-to-target strategy. In this study, we characterise a novel machine learning-based computational method to...

Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission.

Synovial tissue macrophages (STMs) were principally recognized as having a pro-inflammatory role in rheumatoid arthritis (RA), serving as the main producers of pathogenic tumour necrosis factor (TNF). Recent advances in single-cell omics have facilitated the discovery of distinct STM populations, providing an atlas of discrete phenotypic clusters in the context of healthy and inflamed joints. Interrogation of the functions of distinct STM populations, via ex vivo and experimental mouse models, has re-defined our understanding of STM biology, opening up new opportunities to better understand the pathology of the arthritic joint. These works have identified STM subpopulations that form a protective lining barrier within the synovial membrane and actively participate in the remission of RA. We discuss how distinct functions of STM clusters shape the synovial tissue environment in health, during inflammation and in disease remission, as well as how an increased understanding of STM heterogeneity might aid the prediction of clinical outcomes and inform novel treatments for RA.

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis.

Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

Role of booster with BNT162b2 mRNA in SARS-CoV-2 vaccination in patients with rheumatoid arthritis.

Only case reports and small clinical series report the effects of booster vaccination with BNT162b2 in patients with rheumatoid arthritis (RA). We studied 200 patients with RA in clinical remission evaluated with the DAS28. All patients were vaccinated for SARS CoV-2 with the BNT162b2 mRNA vaccine. The value of anti-SARS-CoV 2 Spike RBD IgG antibodies was determined at T1 (3 weeks after first vaccination) and T2 (3 weeks after booster). In addition, patients underwent assessment of lymphocyte subpopulations by flow cytometry analysis before starting the vaccination cycle (T0). Furthermore, the serum antibody levels of 96 health care workers (HCWs) were analyzed for comparison. DAS28 values at T0, T1, and T2 indicated remission or low disease activity in all patients. Levels of anti-SARS CoV-2 IgG at T1 were higher in HCWs than in patients’ groups: 1562.00 BAU WHO/mL [975.00–1632.00] vs 416.00 BAU WHO/mL [110.00, 1581.00], p <0.001. Anti-SARS COV2 IgG levels at T1 and at T2 were slightly lower in patients taking b/tsDMARDs than in patients under csDMARDs. Regression analysis evidenced age, treatment with abatacept (ABA), JAK inhibitors, and rituximab (RTX) as negative predictors of higher anti-SARS CoV-2 IgG levels at T1. Moreover, treatment with anti-IL6, anti-JAK, and anti-tumor necrosis factor (TNF) emerged as positive predictors of higher levels of anti-SARS CoV-2 IgG at T2. Our data show that despite the booster vaccine with BNT162b2, seroconversion in patients with rheumatoid arthritis is influenced by the background therapy, particularly for patients being treated with ABA and RTX.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12026-022-09283-y.

Machine learning-based prediction of relapse in rheumatoid arthritis patients using data on ultrasound examination and blood test

Recent effective therapies enable most rheumatoid arthritis (RA) patients to achieve remission; however, some patients experience relapse. We aimed to predict relapse in RA patients through machine learning (ML) using data on ultrasound (US) examination and blood test. Overall, 210 patients with RA in remission at baseline were dichotomized into remission (n = 150) and relapse (n = 60) based on the disease activity at 2-year follow-up. Three ML classifiers [Logistic Regression, Random Forest, and extreme gradient boosting (XGBoost)] and data on 73 features (14 US examination data, 54 blood test data, and five data on patient information) at baseline were used for predicting relapse. The best performance was obtained using the XGBoost classifier (area under the receiver operator characteristic curve (AUC) = 0.747), compared with Random Forest and Logistic Regression (AUC = 0.719 and 0.701, respectively). In the XGBoost classifier prediction, ten important features, including wrist/metatarsophalangeal superb microvascular imaging scores, were selected using the recursive feature elimination method. The performance was superior to that predicted by researcher-selected features, which are conventional prognostic markers. These results suggest that ML can provide an accurate prediction of relapse in RA patients, and the use of predictive algorithms may facilitate personalized treatment options.

Superb microvascular imaging is as sensitive as contrast-enhanced ultrasound for detecting synovial vascularity in rheumatoid arthritis.

Detection of synovitis is essential for assessing rheumatoid arthritis (RA) activity and predicting prognosis. This study aimed to compare the diagnostic performance of superb microvascular imaging (SMI) with that of contrast-enhanced ultrasound (CEUS) in patients with RA in clinical remission. SMI and CEUS were applied to 63 patients with active RA and 48 patients with RA in clinical remission. Differences in positive synovial vascularity (SV) and its semi-quantitative scale were observed, and the correlations of SMI and CEUS results with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were analyzed. For the 63 joints with active RA, the detection rates of SV as determined by SMI and CEUS were 90.5% (95% CI: 83.0-97.9%) and 93.7% (95% CI: 87.5-99.8%), respectively, with no significant difference observed between the two modalities (t=-1.137; P=0.260). There was good agreement between the two modalities in detecting positive blood flow (Kappa =0.784) and blood flow signal score (Kappa =0.792). For the 48 joints with clinical remission, the detection rates of SV determined by SMI and CEUS were 79.2% (95% CI: 67.2-91.1%) and 83.3% (95% CI: 72.4-94.3%), respectively, with no significant difference found between the two modalities (t=1.000; P=0.322). There was high consistency between the two modalities in detecting positive blood flow (Kappa =0.727) and blood flow signal score (Kappa =0.661). The vascularity scores of SMI and CEUS were positively correlated with CRP, ESR, and RF in the joints with active RA, but not in those with clinical remission. SMI is as sensitive as CEUS for detecting vessels in the synovium and displaying local SV in patients with RA who achieve clinical remission.