A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis.

BACKGROUND: Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases. METHODS: In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses - defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains - at week 12. RESULTS: At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], -2.09±0.18 vs. -0.99±0.26; difference in change, -1.09 [95% confidence interval, -1.73 to -0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups. CONCLUSIONS: Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.).

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

Rheumatoid arthritis.

Rheumatoid arthritis is a chronic, systemic, autoimmune inflammatory disease that mainly affects the joints and periarticular soft tissues. In this Seminar, we provide an overview of the main aspects of rheumatoid arthritis. Epidemiology and advances in the understanding of rheumatoid arthritis pathogenesis will be reviewed. We will discuss the clinical manifestations of rheumatoid arthritis, classification criteria, and the value of imaging in the diagnosis of the disease. The advent of new medications and the accumulated scientific evidence demand continuous updating regarding the diagnosis and management, including therapy, of rheumatoid arthritis. An increasing number of patients are now able to reach disease remission. This major improvement in the outcome of patients with rheumatoid arthritis has been determined by a combination of different factors (eg, early diagnosis, window of opportunity, treat-to-target strategy, advent of targeted disease-modifying antirheumatic drugs, and combination therapy). We will discuss the updated recommendations of the two most influential societies for rheumatology worldwide (ie, the American College of Rheumatology and European Alliance of Associations for Rheumatology) for the management of rheumatoid arthritis. Furthermore, controversies (ie, the role of glucocorticoids in the management of rheumatoid arthritis and safety profile of Janus kinase inhibitors) and outstanding research questions, including precision medicine approach, prevention, and cure of rheumatoid arthritis will be highlighted.

Initial glucocorticoid bridging in rheumatoid arthritis: does it affect glucocorticoid use over time?

OBJECTIVES: To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy. METHODS: Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes. RESULTS: 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months. CONCLUSION: In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years.

Elevated Serum Levels of Zonulin Family Peptides in Anticitrullinated Protein Antibody-Positive At-Risk Individuals Without Arthritis.

OBJECTIVE: Recent advances imply that early events triggering rheumatoid arthritis (RA) occur at mucosal surfaces. We aimed to evaluate whether intestinal permeability is altered in patients at increased risk of RA, and/or predicts the development of clinical arthritis, by measuring serum zonulin family peptides (ZFP) levels, which are shown to reflect intestinal barrier integrity. METHODS: Two independent prospective observational cohorts were studied, including subjects with musculoskeletal symptoms and anticitrullinated protein antibodies (ACPA), but without clinical arthritis at baseline. In Sweden, 82 such at-risk patients were compared to 100 age-matched healthy blood donors. In the UK, 307 at-risk patients were compared to 100 ACPA-negative symptomatic controls. ZFP was measured in baseline sera by enzyme-linked immunoassays. RESULTS: In the Swedish at-risk cohort, ZFP levels were significantly increased in patients compared to controls (mean 41.4 vs 33.6 ng/mL, P < 0.001) and Cox regression analysis showed prognostic value of ZFP for arthritis development (hazard ratio [HZ] 1.04 per ng/mL ZFP increase, 95% CI 1.01-1.07, P = 0.02). Elevated ZFP levels among ACPA-positive at-risk patients compared to symptomatic ACPA-negative controls were confirmed in the UK at-risk cohort (mean 69.7 vs 36.0 ng/mL, P < 0.001), but baseline ZFP were not associated with arthritis development (HR 1.00 per ng/mL ZFP increase, 95% CI 1.00-1.01, P = 0.30). CONCLUSION: Serum ZFP levels are elevated in ACPA-positive at-risk patients when compared to both healthy blood donors and symptomatic ACPA-negative controls. Thus, gut barrier function may be of importance in RA-associated autoimmunity. A possible prognostic value of serum ZFP merits further investigation, preferably in larger prospective cohorts.

Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification.

BACKGROUND: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis. OBJECTIVE: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers. DESIGN: Prospective observational cohort study. SETTING: Single-center, Leeds, United Kingdom. PARTICIPANTS: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred. MEASUREMENTS: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done. RESULTS: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years. LIMITATIONS: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability. CONCLUSION: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Leeds Biomedical Research Centre.

Whole-body MRI for the investigation of joint involvement in inflammatory arthritis.

OBJECTIVES: This study aimed to develop a novel whole-body MRI protocol capable of assessing inflammatory arthritis at an early stage in multiple joints in one examination. MATERIALS AND METHODS: Forty-six patients with inflammatory joint symptoms and 9 healthy volunteers underwent whole-body MR imaging on a 3.0 T MRI scanner in this prospective study. Image quality and pathology in each joint, bursae, entheses and tendons were scored by two of three radiologists and compared to clinical joint scores. Participants were divided into three groups based on diagnosis at 1-year follow-up (healthy volunteers, rheumatoid arthritis and all other types of arthritis). Radiology scores were compared between the three groups using a Kruskal-Wallis test. The clinical utility of radiology scoring was compared to clinical scoring using ROC analysis. RESULTS: A protocol capable of whole-body MR imaging of the joints with an image acquisition time under 20 min was developed with excellent image quality. Synovitis scores were significantly higher in patients who were diagnosed with rheumatoid arthritis at 12 months (p < 0.05). Radiology scoring of bursitis showed statistically significant differences between each of the three groups-healthy control, rheumatoid arthritis and non-rheumatoid arthritis (p < 0.05). There was no statistically significant difference in ROC analysis between MRI and clinical scores. CONCLUSION: This study has developed a whole-body MRI joint imaging protocol that is clinically feasible and shows good differentiation of joint pathology between healthy controls, patients with rheumatoid arthritis and patients with other forms of arthritis.

Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis.

OBJECTIVES: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this. METHODS: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome. RESULTS: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended. CONCLUSIONS: Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update.

BACKGROUND: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

Lymphocyte subset phenotyping for the prediction of progression to inflammatory arthritis in anti-citrullinated-peptide antibody-positive at-risk individuals.

OBJECTIVES: Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T-cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA. METHODS: Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide Antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naïve/memory subsets, inflammation-related cells (IRC), and regulatory cells (Treg/B-reg). Modelling used Logistic/Cox regressions. RESULTS: Of 210 patients included, 93 (44%) progressed to IA, 41/93 (44%) within 12 months (rapid progressors). 5/18 LS were associated with progression (Treg/CD4-naïve/IRC (adjusted p < 0.0001), CD8 (p = 0.021), B-reg (p = 0.015)) and 3 trends (NK-cells/memory-B-cells/plasmablasts).Unsupervised hierarchical clustering using these 8 subsets segregated 3 clusters of patients, one cluster being enriched (63/109(58%)) and one poor (10/45(22%)) in progressors.Combining all clinical and LS variables, forward logistic regression predicted progression with accuracy=85.7% and AUC=0.911, selecting smoking/Rheumatoid-Factor/HLA-Shared-Epitope/Tender-Joint-Count-78 and Treg/CD4-naive/CD8/NK-cells/B-reg/plasmablasts.To predict rapid progression, a Cox regression was performed resulting in a model combining smoking/rheumatoid factor and IRC/CD4-naïve/Treg/NK-cells/CD8+T-cells (AUC=0.794). CONCLUSION: Overall, progression was predicted by specific LS, suggesting potential triggers for events leading to the development of IA, while rapid progression was associated with a different set of subsets.

Ultrasound in anti-CCP+ at-risk individuals without clinical synovitis: development of a novel 6-joint protocol for feasible risk prediction.

OBJECTIVES: To investigate, in anti-cyclic citrullinated peptide antibody positive individuals with musculoskeletal symptoms but no clinical synovitis (CCP+ at-risk), the additional value of ultrasound (US) for the prediction of inflammatory arthritis (IA). Furthermore, to define a concise US protocol for feasible risk prediction. METHODS: Demographic and clinical data were collected in 417 CCP+ at-risk (Leeds CCP cohort) with a baseline US scan assessing synovitis and bone erosions in 36 joints, and a follow-up duration ≥24 months. Multivariable binary regression models for IA development at 24 months evaluated routine clinical variables associated with IA alone ("clinical" model) and combined with a 36-joint US scanning protocol ("clinical-US extended" model). A "clinical-US short" model was developed. RESULTS: At 24 months, 92/417 (22.1%) CCP+ at-risk developed IA (median time: 7 months, IQR : 3-12). The "clinical-US extended" model performed better than the "clinical" model (AUC 0.788 vs AUC 0.731 respectively, p< 0.001) with an odds ratio for IA development of 3.18 (95% IC 1.80-5.63) for US synovitis and 2.54 (95% IC 1.21-5.37) for bone erosions. The "clinical-US short" model, which retained the wrists, knees and MTP5 joints, performed better (AUC 0.782) than the "clinical" model (p< 0.001) and similarly (difference in Akaike information criteria <2) to the "clinical-US extended" model. CONCLUSIONS: US provides valuable information for predicting progression to IA in CCP+ individuals both alone and in addition to clinical variables. US synovitis was associated with a threefold increase risk of IA development. A concise US protocol of 6 joints provides clinically feasible risk prediction in CCP+ at-risk.

Can biomarkers predict successful tapering of conventional disease-modifying therapy in rheumatoid arthritis patients in stable remission?

OBJECTIVES: Specific guidelines for managing RA patients in clinical remission for ≥6 months on cs-DMARDs are lacking. Tapering of treatment is encouraged, however, without validated biomarkers for success. We aimed to assess the rate of sustained remission after 12 months in patients who either (i) followed structured cs-DMARD tapering or (ii) continued therapy, focusing on the added value of biomarkers as predictors of outcome. METHODS: RA patients fulfilling 3v-DAS28CRP<2.6 for ≥6 months on stable cs-DMARD therapy were included. Patients were offered structured tapering, with 117 accepting tapering and 83 continuing therapy. Clinical, ultrasound, immunological (T-cell subsets) and patient-reported outcome (PRO) data were collected. The primary endpoint was the proportion of patients in sustained remission without relapse after 12 months. Regression analyses were used to identify predictors of sustained remission. RESULTS: Of those who tapered, 64% remained in clinical remission after 12 months compared with 80% (p=0.018) of patients on stable treatment. In the tapering group, higher levels of CRP, TJC, % inflammation-related T-cell (IRC) and PROs were associated with flare (all p<0.05), with a trend for total PD (p=0.066). A model predicting sustained remission retained RAQoL, total PD and IRC (85% accuracy, AUROC=0.893, p<0.0001). In the non-tapering group, higher CRP, ESR, SJC and shorter disease duration (all p<0.05) were associated with flare, with no parameter able to predict sustained remission. CONCLUSIONS: In the tapering group, the combination of clinical, PRO, US and T-cell parameters demonstrated added value for predicting sustained remission compared with clinical parameters alone. These data may inform best tapering practice.

Association of circulating lymphocyte subsets with response to IL17i and TNFi in axial spondyloarthritis.

OBJECTIVES: Biologic disease-modifying anti-rheumatic drugs (b-DMARDs) have qualitatively improved the management of axial spondyloarthritis (axSpA), but up to 30-40% of patients do not respond. Although lymphocytes are clearly implicated in the pathology of SpA, circulating lymphocyte subsets (LS) dynamics has been poorly studied. The objective of this pilot study was to comprehensively analyse circulating LS abnormalities in axSpA, and to determine their potential association with response to b-DMARDs. METHODS: Sixty-nine patients with axSpA and 141 control subjects (HC) were included. The clinical features were measured at baseline, and additionally at 6 months in a subgroup of patients who received TNFi (n=36) or IL17i (n=26). Clinical response was defined as a 50% reduction of BASDAI or decrease in ASDAS of 1.1 point. CD4/CD8 T-cells, B-cells and NK-cells and their subsets were analysed by flow cytometry at inclusion. RESULTS: At baseline, alterations in LS were observed in axSpA with reduced/increased frequencies of 10/27 subsets (p<0.003 after correction) and trends for another 5. There was no association of response to bDMARDs with clinical data. Response to IL17i (61% cases) was associated with a higher frequency of NK-cells (p=0.003), trends for change in naïve/memory-CD8+T-cells (p<0.055) and increased expression of KIR3DL2 on Th17-cells (p=0.052). No LS was associated with response to TNFi (69% cases) although trends were observed (CD4+T-cells subsets, higher IL-6R on CD4+/CD8+T-cells). CONCLUSIONS: This pilot work demonstrated a dysregulation of LS in axSpA. The association observed between several LS and clinical response to IL17i (NK/CD8 subsets/Th17-KIR3DL2) was very different to that observed for TNFi (CD4/IL-6R).

TNF-α Regulates Human Plasmacytoid Dendritic Cells by Suppressing IFN-α Production and Enhancing T Cell Activation.

Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. They can produce massive amounts of type I IFNs in response to nucleic acids via TLRs, but they are also known to possess weak Ag-presenting properties inducing CD4+ T cell activation. Previous studies showed a cross-regulation between TNF-α and IFN-α, but many questions remain about the effect of TNF-α in regulating human pDCs. In this study, we showed that TNF-α significantly inhibited the secretion of IFN-α and TNF-α of TLR-stimulated pDCs. Instead, exogenous TNF-α promoted pDC maturation by upregulating costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. Additionally, RNA sequencing analysis showed that TNF-α inhibited IFN-α and TNF-α production by downregulating IRF7 and NF-κB pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-α-treated pDCs induced in vitro higher CD4+ T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-α favors pDC maturation by switching their main role as IFN-α-producing cells to a more conventional dendritic cell phenotype. The functional status of pDCs might therefore be strongly influenced by their overall inflammatory environment, and TNF-α might regulate IFN-α-mediated aspects of a range of autoimmune and inflammatory diseases.

Effects of Disease-Worsening Following Withdrawal of Etanercept or Methotrexate on Patient-Reported Outcomes in Patients With Rheumatoid Arthritis: Results From the SEAM-RA Trial.

BACKGROUND/OBJECTIVE: The effect of treatment withdrawal on patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) whose disease is in sustained remission has not been well described. This analysis aimed to compare PRO changes in patients with RA following medication withdrawal and disease worsening. METHODS: SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis) was a phase 3, multicenter, randomized withdrawal, double-blind controlled study in patients with RA taking methotrexate plus etanercept and in remission (Simple Disease Activity Index ≤3.3). Patient's Global Assessment of Disease Activity, Patient's Assessment of Joint Pain, Health Assessment Questionnaire-Disability Index, and 36-Item Short-Form Health Survey were evaluated for 48 weeks following methotrexate or etanercept withdrawal. Treatment differences for patients with versus without disease worsening were evaluated using a 2-sample t test for continuous end points and log-rank test for time-to-event end points. RESULTS: Of 253 patients, 121 experienced disease worsening and 132 did not. All PRO scores were similar to those of a general population at baseline and deteriorated over time across the study population. The PtGA and Patient's Assessment of Joint Pain values deteriorated less in those on etanercept monotherapy compared with methotrexate monotherapy. More patients with versus without disease worsening experienced deterioration that was greater than the minimal clinically important difference (MCID) for all PROs tested. In patients with disease worsening, PtGA deterioration more than the MCID preceded Simple Disease Activity Index disease worsening. CONCLUSIONS: Etanercept monotherapy showed benefit over methotrexate in maintaining PRO scores. Patients with disease worsening experienced a more rapid worsening of PtGA beyond the MCID versus patients without disease worsening.Categories: autoinflammatory disease, biological therapy, DMARDs, rheumatoid arthritis.

Perceptions and experiences of individuals at-risk of rheumatoid arthritis (RA) knowing about their risk of developing RA and being offered preventive treatment: systematic review and thematic synthesis of qualitative studies.

OBJECTIVES: There is increasing interest in identifying individuals at-risk of rheumatoid arthritis (RA) and initiating early treatment to prevent or delay the onset of arthritis. We aimed to describe the perceptions and experiences of at-risk individuals and to inform the conduct of clinical trials and studies, and clinical practice. METHODS: A systematic review and thematic synthesis of qualitative studies was conducted. Two review authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist and assessed confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative Research approach. RESULTS: Seven studies involving 115 individuals at-risk of developing RA were included. Three major themes (seven subthemes) were identified: understanding the risk of developing RA (knowledge of RA and identification of potential risk factors); preventive interventions to reduce the risk of developing RA (understanding the value and role of preventive interventions, and engagement with preventive interventions); and perceptions of predictive testing for RA (benefits of predictive testing, decision to undertake predictive testing and concerns about predictive testing). Moderate confidence in most review findings was evident. CONCLUSION: While there are clear benefits in informing individuals at-risk of RA about their risk following predictive testing and offering preventive treatment, there are potential barriers to engagement, intensified by the burden of uncertainty. Identification of the optimum approaches for presenting risk information, including the risks and benefits of engaging with preventive interventions, is urgently needed to support individuals at-risk of RA in their decision making. PROSPERO REGISTRATION NUMBER: CRD42021236034.

Dactylitis is an indicator of a more severe phenotype independently associated with greater SJC, CRP, ultrasound synovitis and erosive damage in DMARD-naive early psoriatic arthritis.

OBJECTIVE: To characterise the impact of dactylitis in disease-modifying antirheumatic drug (DMARD)-naive early psoriatic arthritis (PsA). METHODS: Patients with early PsA meeting the classification criteria for PsA (CASPAR) were recruited. Clinical outcomes were recorded, and ultrasonography was conducted to assess grey scale (GS) and power Doppler (PD) synovitis, periarticular cortical bone erosions and enthesitis. The cohort was dichotomised by the presence or absence of dactylitis. RESULTS: Of 177 patients with PsA, those with dactylitis (dactylitic PsA (81/177, 46%)) had higher tender joint count (p<0.01), swollen joint count (SJC) (p<0.001) and C reactive protein (CRP) (p<0.01) than non-dactylitic PsA. Dactylitis was more prevalent in toes (146/214 (68.2%)) than fingers (68/214 (31.8%)); 'hot' dactylitis was more prevalent than 'cold' (83.6% vs 16.4%). Ultrasound (US) synovitis and erosions were significantly more prevalent in dactylitic PsA (p<0.001 and p<0.001, respectively). Exclusion of dactylitis in dactylitic PsA confirmed significantly greater SJC (3 vs 1, p=0.002), US synovitis (GS ≥2: 20.6% vs 16.1%, p<0.001, or PD ≥1: 5.1% vs 3.3%, p<0.001) and erosions (1.1% vs 0.5% joints, p=0.008; 26.1% vs 12.8% patients, p=0.035%) than non-dactylitic PsA. Synovitis (GS ≥2 and/or PD ≥1) occurred in 53.7% of dactylitis. No substantial differences were observed for US enthesitis. CONCLUSION: Dactylitis signifies a more severe disease phenotype independently associated with an increased disease burden with greater SJC, CRP, US-detected synovitis and bone erosions in DMARD-naive early PsA and may be a useful discriminator for early risk stratification.

Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis.

OBJECTIVES: The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis. METHODS: We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). RESULTS: Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not. CONCLUSIONS: HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

Ultrasound subclinical synovitis in anti-CCP-positive at-risk individuals with musculoskeletal symptoms: an important and predictable stage in the rheumatoid arthritis continuum.

OBJECTIVES: To investigate whether anti-CCP2-positive at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis (CCP2+ at-risk) develop US subclinical synovitis before inflammatory arthritis and if US subclinical synovitis can be predicted. METHODS: First, US scans of CCP2+ at-risk individuals who developed inflammatory arthritis ('progressors') were reviewed for subclinical synovitis prior to inflammatory arthritis development. Patients in whom the pre-progression US scan was negative but the scan was conducted >6 months before progression were excluded. Subsequently, regression analyses were performed to identify predictors of US synovitis in CCP2+ at-risk individuals without baseline US abnormalities who had one or more longitudinal US scan and a complete dataset. RESULTS: US subclinical synovitis was detected in one or more scan in 75 of 97 progressors (77.3%) {median time to inflammatory arthritis development from first evidence of US synovitis 26.5 weeks [interquartile range (IQR) 7-60]}, in whom one or more scan was available, excluding those with a negative scan >6 months from inflammatory arthritis development (n = 38). In 220 CCP2+ at-risk individuals with normal baseline US scans, who had one or more longitudinal US scan and a complete dataset, US synovitis was detected in 69/220 (31.4%) [median time to first developing US synovitis 56.4 weeks (IQR 33.0-112.0)]. In the multivariable analysis, only anti-CCP3 antibodies were predictive for the development of US synovitis [odds ratio 4.75 (95% CI 1.97, 11.46); P < 0.01]. CONCLUSIONS: In anti-CCP2+ at-risk individuals, a stage of subclinical synovitis usually precedes the development of inflammatory arthritis. Anti-CCP2+/CCP3+ individuals without clinical or US subclinical synovitis may represent the optimal window of opportunity for intervention to prevent joint disease.

Recently Abstinent Smokers Exhibit Mood-Associated Dopamine Dysfunction in the Ventral Striatum Compared to Nonsmokers: A [11C]-(+)-PHNO PET Study.

INTRODUCTION: Chronic nicotine exposure desensitizes dopamine responses in animals, but it is not known if this occurs in human tobacco smokers. Deficits in dopamine function are likely to make smoking cessation difficult. We used positron emission tomography (PET) brain imaging with the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO to determine if abstinent smokers exhibit less amphetamine-induced dopamine release in the ventral striatum than nonsmokers, and whether this was associated with clinical correlates of smoking cessation. METHODS: Baseline [11C]-(+)-PHNO scans were acquired from smokers (n = 22, 7 female, abstinent 11 ± 9 days) and nonsmokers (n = 20, 7 female). A subset of thirty-seven participants (18 smokers) received oral amphetamine (0.5 mg/kg) three hours before a second [11C]-(+)-PHNO scan. Binding potential (BPND) (i.e., D2/3 receptor availability) was estimated at baseline and postamphetamine in the ventral striatum. Amphetamine-induced percent change in BPND was calculated to reflect dopamine release. Subjects also completed the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: There were no group differences in baseline BPND. Amphetamine-induced percent change in BPND in the ventral striatum was significantly lower in abstinent smokers compared to nonsmokers (p=0.019; d=0.82). Higher CES-D scores were significantly associated with lower ventral striatal percent change in BPND for abstinent smokers (rs=-0.627, p=0.025). CONCLUSIONS: In conclusion, abstinent smokers exhibited significantly less amphetamine-induced dopamine release in the ventral striatum than nonsmokers. In abstinent smokers, worse mood was significantly associated with less striatal dopamine release. Our findings highlight a potential neural mechanism that may underlie negative mood symptoms during early abstinence. IMPLICATIONS: This study combined quantitative PET imaging and an amphetamine challenge to examine striatal dopamine function during early smoking cessation attempts. The findings demonstrate that recently abstinent tobacco smokers exhibit significant, mood-associated striatal dopamine dysfunction compared to nonsmokers. This study advances our knowledge of the neurobiology underlying early quit attempts, and bridges novel neural findings with clinically relevant symptoms of smoking cessation. These results may explain the challenge of maintaining long-term abstinence from smoking, and can lend insight into the development of treatment strategies for smoking cessation.