Transiently increased circulating CD39+FoxP3+ Treg cells predict the clinical response to Methotrexate in Early Rheumatoid Arthritis.

OBJECTIVES: A subset of human circulating FoxP3+ regulatory T cells expresses CD39 (cTreg39+) and hydrolyses pro-inflammatory adenine nucleotides released at inflammatory foci, rendering the anti-inflammatory agent adenosine. Methotrexate (MTX), inhibiting ATIC, enhances the extrusion of adenine nucleotides and may help Treg39+ cells control inflammation. Therefore, we examined the relation of cTreg39+ cells with the effect of MTX in early Rheumatoid Arthritis (eRA). METHODS: Freshly isolated peripheral blood lymphocytes from 98 untreated eRA patients and 98 healthy controls (HC) were examined by cytometry. Twelve months (12m) after initiating MTX, 82 patients were clinically re-evaluated and cytometry was repeated in 40 of them. The effect of MTX on Treg cell potency was assessed in Treg/Tresp cocultures. RESULTS: The baseline (0m) cTreg39+ cell frequency was elevated in eRA above HC levels. Patients who reached low disease activity at 12 months (12m-LDA, DAS28-ESR≤ 3.2, n = 51) had presented with a significantly higher 0m cTreg39+ frequency vs those who did not (n = 31). The 0m cTreg39+ cutoff for attaining 12 m-LDA was 42.0% (Sensitivity=90.4%/Specificity=96.8%). At 12m, the cTreg39+ frequency was no longer elevated but its association with disease activity remained: it was still significantly higher in patients who had reached LDA vs those who had not. In vitro, MTX augmented the Treg39+ cell potency but had no effect on Treg39- cells. CONCLUSION: MTX cooperates with Treg39+ cells and the baseline cTreg39+ frequency predicts the response to MTX in eRA. In addition, the transiently elevated baseline cTreg39+ frequency in eRA may provide a slot for prompt MTX initiation.

Role of IFN-α in Rheumatoid Arthritis.

PURPOSE OF REVIEW: Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. RECENT FINDINGS: We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.

Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past 17 years: Analyses from the IORRA cohort.

OBJECTIVES: The aim of this article is to investigate the mortality rate of patients with early rheumatoid arthritis (RA) over the past 17 years. METHODS: Japanese patients with early RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2001 to 2012 were classified into Groups A (2001-06) and B (2007-12). The standardized mortality ratio (SMR) and 5-year survival rate were calculated. RESULTS: Groups A and B had 1609 and 1608 patients, of which 167 and 178 patients were lost during follow-up and 47 and 45 deaths were confirmed, respectively. The SMR (95% confidence intervals) for Groups A and B were 0.81 (0.59-1.08) and 0.78 (0.57-1.04), respectively, with the condition that all untraceable patients were alive. Assuming that the mortality rate of untraceable patients was twice as high as that of the general population, the SMR was 0.90 (0.68-1.19) for Group A and 0.92 (0.68-1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for Groups A and B, respectively. CONCLUSIONS: The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population. The 5-year survival rate has been stable over the past 17 years.

Inflammatory correlates of the Patient Global Assessment of Disease Activity vary in relation to disease duration and autoantibody status in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the associations between the Patient Global Assessment (PGA) and measures of disease activity in patients with rheumatoid arthritis (RA) in relation to disease duration and autoantibody status. METHODS: 1412 patients from three independent cohorts were studied: a prospective cohort of 810 patients with early RA followed up for 24 months; a cross-sectional cohort of 210 patients with established RA in low disease activity; a cross-sectional cohort of 401 patients with established RA in moderate-to-high disease activity. Correlations of the PGA were analysed by Pearson's coefficients and multivariable linear regression at baseline and at months 6, 12 and 24 in the overall populations and after stratification for autoantibody subgroup and remission status (Boolean remission, PGA near remission and non-remission). RESULTS: In patients with early RA in non-remission, swollen joints correlated independently with the PGA; the correlation became progressively weaker but persisted at all time points in autoantibody-positive patients (adjusted r=0.30-0.12) but lost significance after month 12 in autoantibody-negative patients. Swollen joints independently correlated with the PGA also in near remission until month 12 (adjusted r=0.18-0.16) in autoantibody-positive patients. No independent correlations of inflammatory variables were instead found in patients with established RA irrespective of disease activity and autoantibody status. CONCLUSIONS: In the early phases of RA, particularly in autoantibody-positive patients, inflammatory variables directly correlate with the PGA across different disease activity states. The optimal cut-off values of the PGA capable of identifying absence of disease should be better explored in relation to disease duration and autoantibody status.

Discrepancy between SAA and CRP levels linked to the difference of SAA/CRP ratio in the patients with early rheumatoid arthritis.

OBJECTIVES: Indeed, serum amyloid A (SAA) and C-reactive protein (CRP) reportedly seem to have moderate correlation, but discrepancies between CRP and SAA levels have often been reported in patients with early rheumatoid arthritis (ERA). This study aimed to determine the reasons for this discrepancy. METHODS: ERA patients (n = 206) were enrolled and treated with anti-RA drugs. Clinical features and disease activities were estimated. CRP and SAA levels were monitored, and the SAA/CRP ratio was compared. Correlations between CRP and SAA levels in individuals and between individuals and disease activity scores were examined. RESULTS: In a follow-up study, the SAA/CRP ratio remained almost constant over time in the same patients. However, SAA/CRP ratios differed widely between patients (0.233-106.3). In patients with high SAA/CRP ratios (>6.52), many (26.2%) had abnormal SAA values only. In patients with low SAA/CRP ratios (<6.52), not a few (6.8%) exhibited abnormal CRP values only. CONCLUSIONS: The SAA/CRP ratio remained virtually constant in the same patients but differed dramatically between patients, which clarifies the discrepancy between CRP and SAA levels. CRP is the better marker in low-ratio patients but not in high-ratio patients; the SAA/CRP ratio is critical for its interpretation.

Dysbiosis in the oral microbiomes of anti-CCP positive individuals at risk of developing rheumatoid arthritis.

OBJECTIVES: An increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk). METHODS: Subgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups. RESULTS: At periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05). CONCLUSION: Anti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis.

BACKGROUND: Rheumatoid arthritis (RA) is the most common chronic autoimmune connective tissue disease. However, early RA is difficult to diagnose due to the lack of effective biomarkers. This study aimed to identify new biomarkers and mechanisms for RA disease progression at the transcriptome level through a combination of microarray and bioinformatics analyses. METHODS: Microarray datasets for synovial tissue in RA or osteoarthritis (OA) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by R software. Tissue/organ-specific genes were recognized by BioGPS. Enrichment analyses were performed and protein-protein interaction (PPI) networks were constructed to understand the functions and enriched pathways of DEGs and to identify hub genes. Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks. Biomarkers with high diagnostic value for the early diagnosis of RA were validated by GEO datasets. The ggpubr package was used to perform statistical analyses with Student's t-test. RESULTS: A total of 275 DEGs were identified between 16 RA samples and 10 OA samples from the datasets GSE77298 and GSE82107. Among these DEGs, 71 tissue/organ-specific expressed genes were recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEGs are mostly enriched in immune response, immune-related biological process, immune system, and cytokine signal pathways. Fifteen hub genes and gene cluster modules were identified by Cytoscape. Eight haematologic/immune system-specific expressed hub genes were verified by GEO datasets. GZMA, PRC1, and TTK may be potential biomarkers for diagnosis of early RA. NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158- miR-212-3p/miR-132-3p/miR-129-5p-TTK might be potential RNA regulatory pathways to regulate the disease progression of early RA. CONCLUSIONS: This work identified three haematologic/immune system-specific expressed genes, namely, GZMA, PRC1, and TTK, as potential biomarkers for the early diagnosis and treatment of RA and provided insight into the mechanisms of disease development in RA at the transcriptome level. In addition, we proposed that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158-miR-212-3p/miR-132-3p/miR-129-5p-TTK are potential RNA regulatory pathways that control disease progression in early RA.

A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis.

OBJECTIVES: To evaluate the safety of treatment strategies in patients with early RA. METHODS: Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA). RESULTS: From an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates. CONCLUSION: The study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.

MRI wrist in early rheumatoid arthritis: reduction in inflammation assessed quantitatively during treatment period correlates best with clinical improvement.

OBJECTIVE: To investigate (a) which MR features of inflammation (synovitis, tenosynovitis, perfusion) correlate with clinical/serological features in early rheumatoid arthritis (ERA) before, during and after 1 year of treatment and (b) whether quantitative or semi-quantitative measures of inflammation on magnetic resonance imaging (MRI) provides the highest correlation in this regard. METHOD: One hundred one ERA patients (76 females, 25 males, mean age, 53 ± 12 years) underwent clinical/serological testing and 3 T dynamic contrast-enhanced MRI of the most symptomatic wrist. Seventy-seven of the 101 patients completed 1 year of treatment, followed by repeat MR examination. Clinical/serological parameters were correlated with semi-quantitative/quantitative MR measures of inflammation at baseline, during and after 1 year of treatment. Spearman's correlation was applied. RESULTS: Quantitative measures of inflammation correlated better with clinical/serological parameters than semi-quantitative measures, with the highest correlations being for relative change during treatment. Pain reduction correlated with reduced tenosynovitis volume (r = 0.41). Reduction in disease activity correlated with reduction in synovitis volume (r = 0.66) or synovial perfusion parameters (r = 0.58). Decrease in early morning stiffness correlated with decrease in perfusion parameters (r = 0.46). Reduction in ESR and CRP correlated with decrease in synovial volume (r = 0.40 and r = 0.41, respectively). CONCLUSION: In ERA patients, quantitative assessment of inflammation on MRI correlated better with clinical parameters than semi-quantitative assessment. Relative change during treatment yielded the highest correlation. Decrease in tenosynovitis correlated best with reduction in pain while decrease in synovitis volume and perfusion correlated best with reduction in disease activity, early morning stiffness (perfusion), or serological parameters (synovitis volume).

[Disease-related knowledge acquisition through structured patient information in rheumatoid arthritis (StruPI-RA) : First results of the StruPI-RA study in Germany]. / Krankheitsbezogener Wissenserwerb durch strukturierte Patienteninformation bei Rheumatoider Arthritis (StruPI-RA) : Erste Ergebnisse der StruPI-RA-Studie in Deutschland.

BACKGROUND/OBJECTIVE: The structured patient information for rheumatoid arthritis (StruPi-RA) program was the first standardized outpatient education program in rheumatoid arthritis (RA) in Germany. The main objective of the study was to determine the efficacy of the StruPi-RA program concerning disease-specific knowledge acquisition in patients with early stage RA or after changing the treatment regimen. METHODS: A total of 61 patients were included in a control group design, 32 in the intervention group (IG) and 29 in the control group (CG). Patients of the IG attended 3 modules of 90 min in a structured patient information program (StruPI-RA) including the topics of diagnostics, treatment and living with RA. Patients in the CG only received information material from the German Rheumatism League. The primary target criterion was the disease-related acquisition of knowledge, measured with the patient knowledge questionnaire (PKQ). Data were collected before and after participation in StruPI-RA. RESULTS: The improvement in knowledge in the IG attending the StruPI-RA compared to the CG was significant in time and group comparisons. No influence of disease duration or educational level was observed. The subscale treatment alone showed a significant difference in the group and time comparison. CONCLUSION: Participation in the StruPI-RA program in early RA was associated with a significant increase in disease-specific knowledge compared to the control group of patients. This leads to better decision-making in terms of treatment, a more beneficial doctor-patient communication and better self-management. In the long term an improvement in treatment adherence and quality of life is expected.

Structural and Functional Changes of Hands and Legs in Early Rheumatoid Arthritis.

Background and Objectives: The aim of this study was to assess if there are structural and functional changes of hands and legs already in early rheumatoid arthritis (ERA), compared with the population-based control group. Additionally, we aimed to identify if the changes are symmetrical in hands and legs and if there are factors that are associated with these changes. The study was conducted, and, thus far, the results have been controversial. Materials and Methods: The study group consisted of 83 consecutive patients with ERA and 321 control subjects. Dual-Energy X-Ray Absorptiometry (DXA) machine was used to measure bone, lean and fat mass. Inflammation and bone markers, smoking and nutritional habits were assessed, to evaluate the effects of different factors. The 30-Second Chair Stand Test (30-CST) and the Handgrip Strength Test (HST) were used to estimate muscle strength. Results: The presence of ERA was associated with lower arm, leg lean mass and higher fat mass of arm, compared with control subjects. ERA was also associated with lower mean handgrip in HST and worse muscle strength of legs in the 30-CST. Bone mass changes were not so evident both in arms and legs. Smoking habits did not seem to have relevant effect on bone mass, muscle structural and functional changes, both on hands and legs. In ERA, lean mass of arm and leg was negatively associated with C-reactive protein (CRP). The intake of proteins in ERA was not associated with lean mass changes both in hands and legs. Conclusions: Structural and functional changes of hands and legs are different in ERA. ERA patients had higher fat mass of arm, lower lean mass of arm and leg and, accordingly, decreased muscle function. The lowering of lean mass of arm and leg in ERA was associated with the elevation of CRP.

Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Risk of breast cancer before and after rheumatoid arthritis, and the impact of hormonal factors.

OBJECTIVES: To examine the risk of incident breast cancer in women with rheumatoid arthritis (RA), and the risk of RA in women with a history of breast cancer, taking antihormonal treatment for breast cancer into account. METHODS: Using nationwide Swedish registers, women with new-onset RA diagnosed in 2006-2016 were identified and analysed using a cohort and a case-control design. Each patient with RA was matched on age, sex and place of residence to five randomly selected subjects from the general population. Through register linkages, we collected information on breast cancer, breast cancer risk factors (reproductive history and hormone replacement therapy) and socio-economy. The relative risk of breast cancer after RA was assessed using Cox regression, and the relative risk of RA in women with a history of breast cancer was assessed using conditional logistic regression. RESULTS: The risk of incident breast cancer in women with RA was reduced and the association was not attenuated by adjustment for breast cancer risk factors (HR=0.80, 95% CI 0.68 to 0.93). The risk of RA in women with a history of breast cancer was similarly reduced (OR=0.87, 95% CI 0.79 to 0.95). Women with breast cancer treated with tamoxifen (OR=0.86, 95% CI 0.62 to 1.20) or aromatase inhibitors (OR=0.97, 95% CI 0.69 to 1.37) did not have an increased risk of RA compared with women with breast cancer treated differently. CONCLUSIONS: The decreased occurrence of breast cancer in patients with RA is present already before RA diagnosis; these reduced risks are not readily explained by hormonal risk factors. Adjuvant antihormonal therapy for breast cancer does not seem to increase RA risk.

The earlier, the better or the worse? Towards accurate management of patients with arthralgia at risk for RA.

The favourable long-term results of early treatment in patients with classified rheumatoid arthritis have resulted in an increasing interest in the diseases phases preceding clinical arthritis. The hypothesis to test is that an intervention in these early phases may better prevent or reduce disease persistence than an intervention when arthritis has become clinically manifest. While several placebo-controlled trials are still ongoing, to date there is no firm evidence that this hypothesis truly holds. Therefore, it is important to reflect on the current status of arthralgia preceding clinical arthritis. Inherent to every new field of research, attitudes are conflicting, with opinions propagating innovation (based on the fear of undertreatment) on the one hand, and critical sounds pleading for more restraint (fear of overtreatment) on the other hand. In this Viewpoint, we will examine these divergent opinions, relate them to a preferred ultimate scenario and provide considerations for future studies and daily practice.

Bacterial citrullinated epitopes generated by Porphyromonas gingivalis infection-a missing link for ACPA production.

OBJECTIVES: Porphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA. METHODS: Recombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated. RESULTS: RACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57-71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018). CONCLUSIONS: RACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.

Two-year cost-effectiveness of different COBRA-like intensive remission induction schemes in early rheumatoid arthritis: a piggyback study on the pragmatic randomised controlled CareRA trial.

OBJECTIVES: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients. METHODS: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices. RESULTS: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars. CONCLUSIONS: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment. TRIAL REGISTRATION NUMBER: NCT01172639.

Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis.

OBJECTIVES: To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). METHODS: Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). RESULTS: BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p<0.01). A significant correlation between BE and US synovitis in the MTP5 joints was detected (Cramer's V=0.37, p<0.01). The OR for the development of IA (ever) was highest for the following: BE in >1 joint 10.6 (95% CI 1.9 to 60.4, p<0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1-132.8, p<0.01). CONCLUSIONS: In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in >1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis.

Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial.

OBJECTIVES: We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX. METHODS: Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints. RESULTS: We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX. CONCLUSIONS: Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested. Trial registration number NCT02433184.

Improving the feasibility of MRI in clinically suspect arthralgia for prediction of rheumatoid arthritis by omitting scanning of the feet.

OBJECTIVES: The use of MR-imaging is recommended for the early detection of RA. Next to the small joints of the hands, foot-joints are often involved. Therefore, imaging inflammation of the feet in addition to hands may be informative, but prolongs scan-time and leads to additional costs. We studied the value of MRI of the feet alone and complementary to MRI of the hands in patients with clinically suspect arthralgia (CSA). METHODS: 357 consecutively included CSA patients underwent contrast-enhanced 1.5 T-MRI of hand (MCP2-5 and wrist) and foot (MTP1-5) joints at baseline. Scans were scored for synovitis, osteitis and tenosynovitis. After ⩾1 year follow-up, the development of clinically apparent inflammatory arthritis (IA) was studied. Cox regression was performed and test characteristics were evaluated. Sensitivity analyses were performed for the outcome RA-development (2010-criteria). RESULTS: MRI-detected tenosynovitis of the feet was associated with IA-development, independently from synovitis and osteitis hazard ratio (HR) (95%CI) 4.75 (2.38; 9.49), and independently from ACPA and CRP, HR 3.13 (1.48; 6.64). From all CSA patients, 11% had inflammation in hands and feet, 29% only in hands and 3% only in feet. In line with this finding, the addition of MRI-feet to MRI-hands did not increase the predictive accuracy; the sensitivity remained 77%, while the specificity decreased from 66% to 62%. Sensitivity analyses with RA development as outcome showed similar results. CONCLUSION: Tenosynovitis at the forefeet in CSA predicted IA and RA development. Addition of foot MRI to hand MRI did not increase the accuracy. Foot MRI can be omitted to reduce scan time and costs and increase the feasibility.

Circulating CD19+CD24hiCD38hi regulatory B cells as biomarkers of response to methotrexate in early rheumatoid arthritis.

OBJECTIVE: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional (cTr) B cells have been described in patients with long-standing RA, thus our objective was to examine the frequency and evolution of cTr B cells in the peripheral blood of early RA (ERA) patients. METHODS: Freshly isolated peripheral blood mononuclear cells from 48 steroid- and DMARD-naïve ERA patients with a disease duration of <24 weeks and 48 healthy controls (HCs) were examined by flow cytometry. Co-cultures of isolated memory B cells were established with autologous T cells in the absence or presence of Tr B cells. RESULTS: As compared with HCs, ERA patients demonstrated an increased frequency of cTr B cells. cTr B cells of ERA patients and HCs displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFN-γ and IL-21 production, together with ACPA secretion in autologous B/T cell co-cultures. Basal frequencies of cTr B cells above the median value observed in HCs were associated with a good EULAR response to MTX at 12 months [relative risk 2.91 (95% CI 1.37, 6.47)]. A significant reduction of cTr B cells was observed 12 months after initiating MTX, when the cTr B cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone. CONCLUSION: An increased frequency of regulatory cTr B cells is apparent in untreated ERA and the baseline cTr B cell frequency is associated with the clinical response to MTX at 12 months.