Early Rheumatoid Arthritis Patients Research Articles

At Early Rheumatoid Arthritis Stage, the Infectious Spectrum Is Driven by Non-Familial Factors and Anti-CCP Immunization

Background/Objectives: Patients with rheumatoid arthritis (RA) are prone to develop infections. Methods: Accordingly, 195 untreated early (e)RA patients and 398 healthy controls were selected from women in Tatarstan’s cohort to study infectious history in the anamnesis (four criteria) and in the previous year (16 criteria). Information about annual infections was collected face-to-face from year to year by a qualified rheumatologist/ general practitioner and included the active use of information from medical records. Results: In the anamnesis, tuberculosis, and pneumonia, and in the previous year, respiratory tract infections, skin infections, and herpes simplex virus reactivation incidence were reported to be increased in eRA patients, as well as the event number and duration of acute and chronic tonsillitis. Moreover, more bacterial-suspected upper respiratory infections and urinary tract infections were retrieved in sporadic eRA patients as compared to familial eRA patients. An elevated immunization against CCP prevented respiratory tract infection in those with HSV exacerbation. Finally, associations were retrieved between infection (event number/delay) and RA indices: (i) chronic tonsillitis exacerbations with disease activity and health assessment (HAQ) in familial eRA; (ii) bacterial-suspected upper respiratory infections with the number of swollen and tender joints in sporadic eRA; and (iii) HSV exacerbation with inflammation in eRA patients with negative/low response against CCP. Here, we demonstrate the complex nature of the interplay of RA with specific infections. Conclusions: For the first time, differences in the patterns of annual trivial infections and their links with RA indices were found in cohorts of familial and sporadic cases of the disease. Additionally, for the first time, we identified a remarkable relationship between early RA and exacerbations of chronic tonsillitis, as well as tuberculosis in the patient’s history. Altogether, this study supports the existence of a complex interplay between infections and RA at onset driven by familial status and the presence of anti-CCP Ab at elevated levels.

P103 Centralised pain in early rheumatoid arthritis predicts worse bodily pain outcomes

Abstract Background/Aims Features of centralised pain, encompassing widespread pain and non-pain features such as multisensory hypersensitivity, fatigue, and sleep disturbance are common in RA. We hypothesise that centralised pain in early RA affects response to standard first-line treatment. Methods Prospective cohort study of adults with a clinical diagnosis of RA recruited from the early inflammatory arthritis clinic, Oxford University Hospitals, who completed an online assessment within two weeks of starting a DMARD. Centralised pain was assessed using three measures: the 2016 Fibromyalgia Survey Criteria (0-31), Central Sensitisation Inventory (CSI, 0-100), and PainDetect (0-38). The primary outcome, bodily pain, was assessed using the Short Form-36 Bodily Pain Scale (BPS), where lower scores indicate worse pain severity. During follow-up, participants completed three sets of follow-up questionnaires at 3-, 6- and 12-months. Linear mixed effects models were used to account for repeated measurements and patient variability. Three models were fitted, for an association between baseline values of each centralised pain measure with BPS over time. An interaction between centralised pain scores with time was fitted to assess for effect of the exposure on change over time. Age, sex, and symptom duration at baseline were included as confounding variables. Ethical approval was granted by South Central Oxford B Research Ethics Committee. Results Of 149 participants, 117 (79%) completed follow-up: median (IQR) age 59.8 (24.6) years; 36% male; 30% with symptoms >1 year at baseline. There were no significant baseline differences among those lost to follow-up, apart from a longer symptom duration (53% vs 30% symptom duration >1 year; P = 0.033). At baseline, median (IQR) Fibromyalgia Survey Criteria, CSI, and PainDetect scores were 12 (6), 36 (17), and 14 (9) respectively. The median (IQR) BPS at baseline was 32.5 (22.5). Measures of centralised pain were moderately-to-strongly correlated with each other, and with BPS. Individuals with symptoms for >1 year had higher scores on the PainDetect (P = 0.0015), but not the CSI (P = 0.0545) or Fibromyalgia Survey Criteria (P = 0.672). After adjusting for age, sex, and symptom duration, there was a significant association between centralised pain at baseline and BPS over follow-up, e.g.; for every unit increase in the fibromyalgia survey criteria at baseline, the BPS decreased by 2.40 (95%CI -3.29, -1.49; P < 0.001) points over follow-up. Similar relationships were seen with the CSI and PainDetect scores. Conclusion Centralised pain measures in early RA patients can be indicative of the severity of bodily pain experienced during the subsequent 12 months after starting a DMARD treatment. Recognising and assessing centralised pain in early RA patients may enable us to tailor more effective and individualised treatment regimens. Further studies, especially those utilising neuroimaging and QST, are essential to elucidate the neural mechanisms underlying the impact of centralised pain on treatment outcomes in RA. Disclosure E. Kelleher: None. A.J. Wall: None. M.T. Sanchez-Santos: None. V. Wanigasekera: None. A. Irani (nee Soni): None.

OA27 Molecular divergences in CD4+ T Cells between early and refractory rheumatoid arthritis

Abstract Background/Aims Up to 21% of rheumatoid arthritis (RA) patients remain refractory to available treatments. This represents a clinical challenge due to the lack of efficacious alternatives for refractory RA (rRA) patients. Although CD4+ T cells are paramount in RA pathogenesis, a comprehensive understanding of their roles in rRA versus non-refractory RA has not been characterised. The aim of this study is to dissect the molecular differences in CD4+ T cells across these patient sub-groups and identify novel mechanisms driving rRA, which may inform tailored therapeutic strategies, using single cell multiomic analysis. Methods Primary CD4+ T-cells were isolated from PBMCs obtained from 3 rRA patients (defined as per EULAR definition of difficult-to-treat RA) and 3 treatment-naïve, early RA (ERA) patients, all seropositive with active disease (DAS28-ESR > 3.2), collected as part of the PRECISE-RA programme. Following nuclei extraction, the 10x Genomics Multiome ATAC + Gene Expression assay was used to simultaneously determine the transcriptional and chromatin landscapes from individual cells. Results Patient characteristics are reported in Table 1. 8,215 T-cells cells were clustered into 11 distinct cell states, which showed a trend towards diminished Tregs and modulated effector memory (TEM)/Th17 phenotype expressions in rRA compared to ERA patients. In ERA, expression of INPP4B, pivotal for cell growth and survival, was upregulated within naïve CD4+ T-cell subsets. ITGA4, crucial in leukocyte migration and adhesion, was elevated within a subset of naïve CD4+ T cells in early RA. ZEB2 exhibited increased expression within CD4 TEM/Th17 phenotype cells, potentially implicating divergent cellular differentiation, and migratory pathways within early RA contexts. Next, we utilised the multiomic nature of the data to functionally annotate GWAS variants, by creating peak-gene maps and overlaying RA risk SNPs. For example, an RA susceptibility SNP mapping to an intron of ANKRD55, rs7731626, was linked to the novel RA causal gene IL6ST. Furthermore, the RA SNP rs71508903, previously assigned to the ARID5B gene, was linked to the RTKN2 promoter, elucidating potential avenues for further exploration into RA pathogenesis. Conclusion These findings, to be validated in a larger cohort, suggest distinct biological mechanisms driving rRA and may help identify novel biomarkers and therapeutic avenues. Disclosure S.L. Smith: None. S. Rossi: None. R. Shukla: None. Y. Tan: None. A. Ariff: None. I. Lazar: None. K. Patel: None. C.F. Yap: None. N. Nair: None. S. Eyre: None. M.H. Buch: None. M.H. Buch: None. P. Martin: None. G. Orozco: None.

Temporomandibular dysfunction and bruxism in patients with early rheumatoid arthritis and at-risk patients: a cross-sectional study

What is the prevalence of temporomandibular dysfunction in patients with early rheumatoid arthritis and individuals at risk of rheumatoid arthritis? 3 groups (of 50 participants each) were examined for a possible TMD diagnosis: 1. patients with early rheumatoid arthritis, 2. at-risk individuals, and 3. healthy controls. A possible association with bruxism, determined on the basis of self-reporting and clinical features, was also examined. At-risk patients had a higher prevalence of TMD pain diagnoses compared to healthy controls (p = 0.046). Within the early rheumatoid arthritis group, seronegative patients had a higher prevalence of TMD pain diagnoses than seropositive patients (p = 0.048). No further differences in the prevalence of TMD diagnoses were found between the groups. Participants with a TMD pain diagnosis were more often diagnosed with probable sleep bruxism than those without a TMD pain diagnosis. The prevalence of TMD pain is increased in individuals at risk of rheumatoid arthritis and seronegative early rheumatoid arthritis patients, and is associated with signs of bruxism.

Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis.

To determine whether patient reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established rheumatoid arthritis (RA). All early RA patients (n = 557) from the tREACH-trial and established RA patients (n = 188) from the TARA-trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: Health Assessment Questionnaire Disability Index(HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form(SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status(remission, low disease activity and active disease) using linear mixed models and standardised response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated. HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low. HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor. tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754).

Prednisone use, disease activity and the occurrence of hyperglycaemia and diabetes in patients with early rheumatoid arthritis: a 10-year subanalysis of the BeSt study

ObjectivesTo assess whether prednisone use and/or disease activity score (DAS) are associated with the development of hyperglycaemia and diabetes in rheumatoid arthritis (RA).MethodsWe included 504 non-diabetic early RA patients from...

Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes

BackgroundTo describe the evidence of methotrexate (MTX) initiation strategies in patients with rheumatoid arthritis (RA) and, in the case of non-responders, analyse the efficacy and safety of route and dose optimisation.MethodsWe conducted a comprehensive scoping review of randomised controlled trials according to PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. PubMed, EMBASE, and Cochrane were searched without language restriction, and hand searches of relevant articles were examined.ResultsWe identified 1,367 potentially eligible studies, of which 12 were selected based on the titles and abstracts and then on the full-length articles. In naïve-MTX patients, a linear dose-response relationship for starting dose was found between 5 mg/m2/week (7.5–10 mg/week) and 10 mg/m2/week (15–22 mg/week), without toxicity correlation. A higher initial dose of MTX (25 mg vs. 15 mg) was more effective, resulting in fewer dose increases due to ineffectiveness and more dose reductions due to higher remission rates. There was also a trend towards increased gastrointestinal toxicity. Comparing different routes of administration of MTX, subcutaneous MTX showed a statistically higher ACR20 response (85%) in comparison with oral MTX (77%) (p < 0.05). The clinical efficacy and safety of accelerated and conventional start MTX regimens were comparable between 7.5 and 15 mg with a 2,5 mg dose increase every two weeks. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response and sustained remission rate than other strategies. In MTX non-responders, optimisation to SC MTX was associated with improvements in ACR20 and ACR50 rates with similar toxicity between groups. In the early RA patients subgroup, SC MTX showed higher ACR20 response rates than oral MTX, and intensive oral methods have a much higher sustained remission rate, shorter mean time to remission, and better clinical disease activity measures than conventional treatments.ConclusionsHigher starting doses of MTX and initial subcutaneous MTX made better performance in improving the ACR20 response, although the clinical effectiveness and safety of other MTX start regimens are comparable. This scoping review provides evidence in support of optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment in RA patients has failed.

Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis

BackgroundDisease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.MethodsThis study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.ResultsPatients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.ConclusionsTreatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

Correlation Of Lipid Profile and Das28 Score of Early Rheumatoid Arthritis Patients on Conventional Synthetic Dmards

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and a higher risk of cardiovascular diseases. The relationship between RA disease activity, lipid profiles, and the impact of disease-modifying antirheumatic drugs (DMARDs) on these parameters is an area of ongoing research. Objective: This study aimed to investigate the correlation between lipid profiles and the Disease Activity Score in 28 joints (DAS-28) in patients with early RA who were on conventional synthetic DMARDs. Methods: In this cross-sectional study, 30 RA patients from a rheumatology department were enrolled over six months. The study included adults aged 30-70 years, of both genders, who had been on DMARDs for at least 6 months. Exclusion criteria included fracture of the affected joint, pregnancy, use of steroids or lipid-lowering agents, and heavy smoking. Data on demographics, disease duration, type of DMARDs, and lipid profiles were collected. The DAS-28 score was calculated for each patient. Statistical analysis was performed using SPSS Version 25, with Pearson’s Correlation coefficient used to measure relationships between variables. Results: The cohort consisted of 53.3% males and 46.7% females, with a mean age of 48.23 years. The majority (76.7%) were rheumatoid factor positive. The most commonly used DMARD was Methotrexate (46.7%). The study found strong negative correlations between DAS-28 scores and lipid levels: total cholesterol (Pearson's r = -0.837), triglycerides (r = -0.759), LDL (r = -0.720), and HDL (r = -0.689). BMI showed a significant positive correlation with DAS-28 (r = 0.711). A notable negative correlation was observed between the duration of DMARD use and DAS-28 scores (r = -0.777). Conclusion: The study indicates a significant correlation between lipid profiles and disease activity in RA patients on DMARDs. The findings suggest that effective RA management with DMARDs could influence lipid metabolism and potentially reduce cardiovascular risks. These insights are crucial for developing comprehensive RA treatment strategies that encompass both joint health and cardiovascular considerations.

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21−/low double-negative B cells

BackgroundInvolvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21−/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21+ and CD21−/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction.MethodsSeventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry.ResultsCompared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21+ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21+CD27+ subsets and CD21−/low CD27+IgD+ subset. The only B cell subset found to associate with clinical factors was the CD21−/low double-negative (DN, CD27−IgD−) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21−/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL).ConclusionsCartilage destruction in eRA patients was associated with an expanded proportion of CD21−/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21−/low DN in RA pathogenesis.

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

To discover autoantibodies to non-modified proteins associated with the presence/absence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). The autoantibody repertoire of 80 ACPA negative and 80 ACPA positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls. The relationship between the four autoantibodies and lung abnormalities on high-resolution computed tomography (HRTC) was examined in 93 early RA patients from LURA cohort. Association between the autoantibodies, smoking and MHC class II alleles was assessed by logistic regression analysis. : Anti-ANOS1 and anti-MURC IgG levels were associated with ACPA-positive status (OR = 3.02; 95% CI 1.87-4.89; and OR = 1.86; 95% CI 1.16-2.97, respectively) and increased in ACPA-positive patients compared with controls. Anti-ANOS1 IgG was associated with smoking habit (OR = 2.11; 95% CI 1.22-3.69) and anti-MURC IgG with the presence of the MHC class II "shared-epitope" genes (OR = 1.95; 95% CI 1.11-3.46). Anti-TSPYL4 IgG was associated with ACPA-negative (OR = 0.41; 95% CI 0.19-0.89). Anti-TSPYL4 IgG and anti-MAP2K6 IgG levels were increased in the ACPA-negative patients compared with controls. Presence of anti-MAP2K6 IgG and anti-TSPYL4 IgG correlated negatively with HRCT-defined lung abnormalities. These four autoantibodies may be useful in diagnostics and in predicting clinical phenotypes of RA.

Micro-RNA content of circulating extracellular vesicles in early rheumatoid arthritis as biomarkers and mediators of methotrexate efficacy.

Extracellular vesicles (EVs) are abundant in body fluids, contributing to intercellular signalling by transferring cargo that includes microRNAs (miRs) - themselves implicated in pathobiology. For the first time we evaluated the potential of EV miRs to contribute diagnostic information in early RA, predict methotrexate (MTX) efficacy or shed light on the drug's mechanism of action. 798 miRs isolated from serum-derived EVs of 46 patients with untreated RA, 23 with untreated polymyalgia rheumatica (PMR; inflammatory disease control group) and 12 in whom significant inflammatory disease had been excluded (non-inflammatory controls; NICs) were profiled (Nanostring); the same measurements were made for RA patients after 6 months' MTX treatment. Analyses took multiple testing into account. 28 EV miRs were robustly differentially expressed between early RA (but not PMR) patients and NICs after correction for age and sex, suggesting discriminatory value. Cross-validated partial least squared-discriminant analysis also indicated the predictive potential of a distinct baseline EV miR signature with respect to MTX-induced remission at 6 months. The change in expression of 13 miRs over the course of MTX treatment differed significantly between responders and non-responders, and four of those exhibiting increased relative abundance amongst responders have known roles in regulating the pathogenic potential of synovial fibroblasts, namely miR-212-3p, miR-338-5p, miR-410-3p, and miR-537. Our data highlight the potential of serum EV miRs as diagnostic and therapeutic biomarkers, highlighting a novel potential mechanism via which MTX may exert its therapeutic effect in early RA that warrants further investigation.

B-104 Comparison of the Performance Characteristics of the Third Generation Anti-Cyclic Citrullinated Peptide CCP3.1 IgG/IgA and CCP3 IgG Assays

Abstract Background Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases. Anti-citrullinated protein antibody (ACPA) is the most specific serological biomarker for RA and is associated with significantly more disease activity compared to rheumatoid factor (RF). Improved autoantibody detection relied in the generation of tests against cyclic citrullinated peptide (CCP), a subset of ACPA. The 3rd generation anti-CCP IgG antibody (CCP3) emerged with increased sensitivity compared to the earlier versions. More recently, CCP3.1 with conjugate to detect IgA antibodies in addition to the usual IgG antibodies became available. This is described to exhibit enhanced sensitivity due to early RA patients producing IgA antibodies to CCP3 in the absence of IgG. In this study, we evaluated the diagnostic characteristics of CCP3.1 and its association with disease severity in comparison to CCP3. Methods Our cohort included a total of 331 subjects submitted for RA panel or independent antibody testing. Chart review revealed 136 clinically defined RA- positive and 195 RA- negative patients. Residual sera from these patients were tested for RF (Roche Diagnostics, Indianapolis, US), CCP3 and CCP3.1 (Inova Diagnostics, San Diego, US) antibodies. Clinical performance characteristics at the manufacture-suggested cut-off and association with disease severity were assessed and compared between the two assays. Results The overall diagnostic accuracy was comparable between the two assays with CCP3 exhibiting an area under the curve (AUC) of 0.879, 95% CI: 0.836–0.922, and CCP3.1 showed an AUC of 0.890, 95% CI: 0.849–0.931. CCP3 displayed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 78.7%, 90.8%, 85.6% and 85.9% respectively. CCP 3.1 displayed an equivalent performance with 77.9% sensitivity, 93.3% specificity, 89.1% PPV and 85.8% NPV. Both assays showed an excellent agreement with a positive percent agreement of 92.0% and negative percent agreement of 98.7%. There was a strong quantitative correlation between the two assays (Spearman correlation coefficient, r = 0.864, P &amp;lt; 0.001). Paired t test showed significantly higher titers of CCP3 (mean:118, median:145) compared to CCP3.1 (mean:110, median: 108) in RA patients. RF and CCP3.1 combination yielded a slightly greater specificity (99.0%), positive likelihood ratio (65.9) and odds ratio (201.7) compared to the RF and CCP3 combination (specificity: 98.5%, positive likelihood ratio: 44.5, odds ratio: 138.4). Nine early-RA patients (with symptom onset &amp;lt;6 months of diagnosis) were detected by both assays and displayed comparable titers (CCP3.1, mean:138, median:149; CCP3, mean:149, median:161). Out of 60 RA patients exhibiting more severe disease course with the presence of bone erosions, 50 of them were detected by CCP3.1 (mean:125, median:146) and 51 were detected by CCP3 (mean:139, median:151) and the titers were comparable. Conclusion CCP3 and CCP3.1 assays displayed comparable performance for detection of RA and correlated similarly with the disease severity. In our study cohort that mainly comprised of RA patients diagnosed &amp;gt;6 months after symptoms onset, addition of IgA isotype showed no added value but did not compromise performance.

The dichotomy of glucocorticosteroid treatment in immune-inflammatory rheumatic diseases: an evidence-based perspective and insights from clinical practice.

Glucocorticosteroids (GCs) are the most used anti-inflammatory and immunosuppressive drugs due to their effectiveness in managing pain and disease modification in many immune-inflammatory rheumatic diseases (IRDs). However, their use is limited because of adverse effects (AEs). The authors analyzed recent studies, including randomized controlled trials (RCTs), observational, translational studies and systematic reviews, providing an in-depth viewpoint on the benefits and drawbacks of GC use in rheumatology. Glucocorticosteroids are essential in managing life-threatening autoimmune diseases and a cornerstone in many IRDs given their swift onset of action, necessary in flares. Several RCTs and meta-analyses have demonstrated that when administered over a long time and on a low-dose basis, GC can slow the radiographic progression in early rheumatoid arthritis (RA) patients by at least 50%, satisfying the conventional definition of a disease-modifying anti-rheumatic drug (DMARD). In the context of RA treatment, the use of modified-release prednisone formulations at night may offer the option of respecting circadian rhythms of both inflammatory response and HPA activation, thereby enabling low-dose GC administration to mitigate nocturnal inflammation and prolonged morning fatigue and joint stiffness. Long-term GC use should be individualized based on patient characteristics and minimized due to their potential AEs. Their chronic use, especially at medium/high dosages, might cause irreversible organ damage due to the burden of metabolic systemic effects and increased risk of infections. Many international guidelines recommend tapering/withdrawal of GCs in sustained remission. Treat-to-target (T2T) strategies are critical in setting targets for disease activity and reducing/discontinuing GCs once control is achieved. Glucocorticosteroids' use in treating IRDs should be judicious, focused on minimizing use, tapering and discontinuing treatment, when possible, to improve long-term safety. Glucocorticosteroids remain part of many therapeutic regimens, particularly at low doses, and elderly RA patients, especially with associated chronic comorbidities, may benefit from long-term low-dose GC treatment. A personalized GC therapy is essential for optimal long-term outcomes.

CD64 as novel molecular imaging marker for the characterization of synovitis in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is one of the most prevalent and debilitating joint diseases worldwide. RA is characterized by synovial inflammation (synovitis), which is linked to the development of joint destruction. Magnetic resonance imaging and ultrasonography are widely being used to detect the presence and extent of synovitis. However, these techniques do not reveal the activation status of inflammatory cells such as macrophages that play a crucial role in synovitis and express CD64 (Fc gamma receptor (FcγR)I) which is considered as macrophage activation marker.ObjectivesWe aimed to investigate CD64 expression and its correlation with pro-inflammatory cytokines and pro-damaging factors in human-derived RA synovium. Furthermore, we aimed to set up a molecular imaging modality using a radiolabeled CD64-specific antibody as a novel imaging tracer that could be used to determine the extent and phenotype of synovitis using optical and nuclear imaging.MethodsFirst, we investigated CD64 expression in synovium of early- and late-stage RA patients and studied its correlation with the expression of pro-inflammatory and tissue-damaging factors. Next, we conjugated an anti-CD64 antibody with IRDye 800CW and diethylenetriamine penta-acetic acid (DTPA; used for 111In labeling) and tested its binding on cultured THP1 cells, ex vivo RA synovium explants and its imaging potential in SCID mice implanted with human RA synovium explants obtained from RA patients who underwent total joint replacement.ResultsWe showed that CD64 is expressed in synovium of early and late-stage RA patients and that FCGR1A/CD64 expression is strongly correlated with factors known to be involved in RA progression. Combined, this makes CD64 a useful marker for imaging the extent and phenotype of synovitis. We reported higher binding of the [111In]In-DTPA-IRDye 800CW anti-CD64 antibody to in vitro cultured THP1 monocytes and ex vivo RA synovium compared to isotype control. In human RA synovial explants implanted in SCID mice, the ratio of uptake of the antibody in synovium over blood was significantly higher when injected with anti-CD64 compared to isotype and injecting an excess of unlabeled antibody significantly reduced the antibody-binding associated signal, both indicating specific receptor binding.ConclusionTaken together, we successfully developed an optical and nuclear imaging modality to detect CD64 in human RA synovium in vivo.

Rheumatoid arthritis specific autoimmunity in the lung before and at the onset of disease.

The lung is implicated as a site for breaching tolerance prior to onset of seropositive RA. To substantiate this, we have investigated lung-resident B cells in bronchoalveolar lavage (BAL) samples from early untreated RA patients (n=9) and anti-citrullinated protein antibody (ACPA)-positive individuals at risk of developing RA (n=3). Single B cells (n=7680) were phenotyped and isolated from BAL of individuals during the risk-RA phase and at RA diagnosis. The Immunoglobulin variable region transcripts were sequenced and selected for expression as monoclonal antibodies (n=141). Monoclonal ACPAs were tested for reactivity patterns and binding to neutrophils. By our single cell approach, we found significantly increased proportions of B lymphocytes in autoantibody-positive as compared to negative individuals. Memory and double negative (DN) B cells were prominent in all subgroups. Upon antibody re-expression, seven highly mutated citrulline autoreactive clones originating from different memory B cell subsets where identified, both in at-risk and early RA patients. Lung IgG variable gene transcripts from ACPA-positive individuals carry frequent mutation-induced N-linked Fab glycosylation sites (p<0.001), often in the framework-3 of the variable region. Two of the lungs ACPAs bound to activated neutrophils, one from an at-risk individual and one from early RA. We conclude that T cell driven B cell differentiation, resulting in local class switching and somatic hypermutation are evident in lungs before, as well as in, early stages of ACPA-positive RA. Our findings add to the notion of lung mucosa being a site for initiation of the citrulline autoimmunity preceding seropositive RA. This article is protected by copyright. All rights reserved.

Analysis of Novel Immunological Biomarkers Related to Rheumatoid Arthritis Disease Severity.

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the most frequently used rheumatoid arthritis (RA) diagnostic markers, but they are unable to anticipate the patient's evolution or response to treatment. The aim of this study was to identify possible severity biomarkers to predict an upcoming flare-up or remission period. To address this objective, sera and anticoagulated blood samples were collected from healthy controls (HCs; n = 39) and from early RA (n = 10), flare-up (n = 5), and remission (n = 16) patients. We analyzed leukocyte phenotype markers, regulatory T cells, cell proliferation, and cytokine profiles. Flare-up patients showed increased percentages of cluster of differentiation (CD)3+CD4- lymphocytes (p < 0.01) and granulocytes (p < 0.05) but a decreased natural killer (NK)/T lymphocyte ratio (p < 0.05). Analysis of leukocyte markers by principal component analysis (PCA) and receiver operating characteristic (ROC) curves showed that CD45RO+ (p < 0.0001) and CD45RA+ (p < 0.0001) B lymphocyte expression can discriminate between HCs and early RA patients, while CD3+CD4- lymphocyte percentage (p < 0.0424) and CD45RA+ (p < 0.0424), CD62L+ (p < 0.0284), and CD11a+ (p < 0.0185) B lymphocyte expression can differentiate between flare-up and RA remission subjects. Thus, the combined study of these leukocyte surface markers could have potential as disease severity biomarkers for RA, whose fluctuations could be related to the development of the characteristic pro-inflammatory environment.

Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis.

To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short- and long-term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. No individual SNP reached genome-wide significance (P < 5 × 10-8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96-1.01)] or at 3 years [RR = 0.96 (0.93-1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15-0.75) at 1 year and 0.14 (0-0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA.

Impact of adverse drug reactions on the treatment pathways of early rheumatoid arthritis patients: a prospective observational cohort study

ABSTRACT Background Several patient characteristics may be of influence on treatment pathways of rheumatoid arthritis (RA) patients in clinical practice. The aim of this study is to analyze treatment pathways of early RA patients stratified for gender and adverse drug reaction (ADR) occurrence. Research design and methods Treatment pathways of patients included in the DREAM-RA treat-to-target cohort I between 16th of July 2006–30th of April 2020 were assessed. Treatment pathways were visualized in Sankey diagrams. Follow-up time, duration per treatment and the number of treatments received were stratified for gender and ADR occurrence and analyzed. Independent t-tests and chi-square tests were performed where applicable. Results Treatment pathways of 372 patients (follow-up: 2488.4 years, mean 6.7 ± 3.7 years) were analyzed. The Sankey diagrams visualize that treatment pathways became increasingly varied and complex over time. No significant differences were found when comparing female patients and male patients. However, the average treatment duration was shorter in patients with ADRs (1.8 vs. 2.7 years, p < 0.05), and the number of treatments higher (3.5 vs. 2.5, p < 0.05). Conclusions Treatment pathways increase in complexity over time. Differences were found between patients with and without ADRs, with patients that experience ADRs receiving more and shorter treatments.

Joint tenderness at 3 months follow-up better predicts long-term pain than baseline characteristics in early rheumatoid arthritis patients.

To investigate pain course over time and to identify baseline and 3-month predictors of unacceptable pain with or without low inflammation in early RA. A cohort of 275 patients with early RA, recruited in 2012-2016, was investigated and followed for 2 years. Pain was assessed using a visual analogue scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain >40, and low inflammation as CRP <10 mg/l. Baseline and 3-month predictors of unacceptable pain were evaluated using logistic regression analysis. After 2 years, 32% of patients reported unacceptable pain. Among those, 81% had low inflammation. Unacceptable pain, and unacceptable pain with low inflammation, at 1 and 2 years was significantly associated with several factors at 3 months, but not at baseline. Three-month predictors of these pain states at 1 and 2 years were higher scores for pain, patient global assessment, and the health assessment questionnaire, and more extensive joint tenderness compared with the number of swollen joints. No significant associations were found for objective inflammatory measures. A substantial proportion of patients had unacceptable pain with low inflammation after 2 years. Three months after diagnosis seems to be a good time-point for assessing the risk of long-term pain. The associations between patient reported outcomes and pain, and the lack of association with objective inflammatory measures, supports the uncoupling between pain and inflammation in RA. Having many tender joints, but more limited synovitis, may be predictive of long-term pain despite low inflammation in early RA.