Objective A novel population of B helper cells, phenotypically CD4+CXCR5−PD-1hi, has been described in the synovial tissues and peripheral blood of seropositive RA patients, and termed ‘peripheral helper T’ (Tph) cells. Contrary to CD4+CXCR5+PD-1hi follicular helper T (Tfh), Tph cells are not located in lymphoid organs but accumulate in inflamed tissues. Our objective was to study the frequency of circulating Tph (cTph) and circulating Tfh cell counterparts (cTfh) in patients with early RA (eRA). Methods Freshly isolated peripheral blood mononuclear cells from 56 DMARD-naïve eRA patients and 56 healthy controls were examined by flow cytometry. Autologous cocultures of naïve or memory B cells were established with isolated peripheral blood Tph or Tfh cells. Results Seropositive (RF+ and/or ACPA+, n = 38) but not seronegative eRA patients (n = 18) demonstrated increased frequencies and absolute numbers of cTph and cTfh cells. cTph but not cTfh cells expressed CCR2. Those eRA patients who experienced a significant clinical improvement at 12 months demonstrated a marked decrease of their cTph cell numbers whereas their cTfh cell numbers remained unchanged. Both isolated Tph and isolated Tfh cells were able to induce maturation of memory B cells, whereas only Tfh cells could differentiate naïve B cells. Conclusion Two populations of PD-1hiCD4 T cells with distinct phenotype and B cell helping capacity are increased in the peripheral blood of seropositive eRA patients. Whereas cTph cells are present only in patients with an active disease, cTfh cells seem to be constitutively elevated.
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.
BackgroundA novel population of CD4 +T cells with B cell helping capacity has been described in the synovial tissues and peripheral blood of seropositive RA patients with an established disease, and termed ‘peripheral helper’ (Tph) cells. (Rao DA et al, Nature 2017) Tph cells are characterised by the lack of CXCR5 together with a bright expression of PD-1 (CD4 +CXCR5-PD-1hi T cells). As opposed to CD4 +CXCR5+PD-1hi follicular helper T cells (Tfh), Tph cells are not located in lymphoid organs but accumulate in inflamed tissues. Tph cell numbers have not been previously examined in early RA (eRA).ObjectivesTo study the frequency of circulating CD3 +CD4+CXCR5-PD-1hi Tph cells (cTph), in patients with eRA.MethodsPeripheral blood was drawn from DMARD-naïve early RA patients (eRA) (2010 ACR criteria) with a disease duration <24 weeks (n=42), and healthy controls (HC) matched for age and gender (n=42). For comparison, blood was also drawn from 66 patients with established RA (disease duration >2 years), 45 patients with Spondyloarthritis (SpA), and their age and gender-matched HC (one HC per patient). In addition, synovial fluid from 7 patients with established RA and 3 patients with SpA was examined. Established RA patients were receiving low-dose oral methotrexate and were naïve for biological agents. SpA patients were receiving NSAIDs, low-dose oral methotrexate and/or sulphasalazine and were naïve for biologicals. After isolation by Ficoll-Hypaque gradient, PBMCs were stained with antibodies to CD3, CD4, CXCR5, ICOS and PD-1, and examined by flow cytometry.ResultsThe frequency of circulating CXCR5- cells gated for CD4 +T cells was not different among the studied groups. In contrast, eRA patients demonstrated an increased frequency of circulating CD4 +CXCR5-PD-1hi Tph and CD4 +CXCR5-PD-1hiICOS+ T cells. When examining seropositive (RF +and/or ACPA+, n=25) and seronegative eRA patients (RF- and ACPA-, n=17) separately, it was evident that the above described alterations were only apparent in seropositive eRA. Likewise, increased cTph numbers were observed in seropositive (n=47) but not seronegative (n=19) established RA, and not in SpA patients (n=45), which is consistent with data reported by Rao et al. Interestingly, this increased cTph cell frequency was observed only in seropositive RA patients with an active disease (DAS28 >2.6, n=24), whereas the numbers of cTph cells in established RA patients who had achieved remission (DAS28 <2.6, n=23) were not different from HC. Furthermore, Tph cells were present in the synovial fluid of seropositive RA (n=4) but not of seronegative RA (n=3) or SpA (n=3).ConclusionsTph cells may play an important role in the pathogenesis of seropositive but not seronegative RA. An increased cTph cell frequency is a marker of active, seropositive RA.Reference[1] Rao DA, et al. Nature2017;542(7639):110–114.Disclosure of InterestNone declared
Background:Inflammatory arthralgia (IA) onset is a common rheumatology consultation. Identifying predictors for chronic arthritis (CA) development by ultrasonography (US) may provide early diagnosis and treatment in order to prevent progression of the disease.Objectives:Establishing US findings that can be related to CA development in patients with inflammatory arthralgia without arthritis. Assess the link among US, clinical and biochemical parameters.Methods:A prospective longitudinal study of a cohort of patients with IA. Patients with less tan one year of AI evolution and involvement of at least one small joint from hands or feet were included. Patients with arthritis, osteoarthritis, fibromyalgia and those treated with DMARDs or steroids were excluded. We made a 6-monthly evaluation for 2 years and recorded the CA development during that period. The number of painful joints (PJC) and biochemical data (CRP, ESR) were assessed at the first visit. A blind US exploration was made using a MyLabTwice (Esaote) equipment with a 5-13MHz probe for greyscale (GS) and Power Doppler (PD), examining 36 joints (radio-carpals, MCP, IPP, 2nd-5th MTP, elbows, shoulders and knees) and 14 tendon compartments (2nd, 4th and 6th wrist extensors, 3rd and 4th finger flexors and posterior tibial and fibularis tendons), giving an overall score of GS, PD (0-3) and number of erosions by rating the presence of sinovitis on each location.We performed a descriptive analysis based on the frequencies of qualitative variables and mean±SD/median (IQR) of quantitative variables, comparing the characteristics between patients with and without CA progression by Chi-Square and Mann-Whitney U tests. Also, the possible relationship of those variables and the disease progression was assessed by a univariate binary logistic regression analysis.We designed a reduced US examination (RUE) selecting the most affected locations and those with greatest differencies between groups in the statistical analysis.Results:Of the 49 patients included, 21 (42.9%) progressed to CA. 87% were females and 71.4% non-smokers with a mean age of 44 ± 12 years. The median of PJC was 4 (1-9). RF and/or CCPA were positive in 18.4% and 34.7% had high CRP/ESR. The suggested RUE included carpi, 2nd-4th MCP, 2nd-3rd IPP, 2nd and 5th MTP, 4th and 6th wrist extensors and fibularis tendons. Scores and comparative analysis within subgroups are listed in Table 1. The RUE score was significantly greater in both GS (OR 1.4, CI 95%) and PD (OR 1.3, CI 95%) on patients that progressed to CA.Table 1.GS and PD scores compared by main locations and RUE-Score [showed as median (IQR)].ScoreNo progression (n=28)Progression to IA (n=21)PGS global5.5 (2-11)11 (7-15)0.005*PD global2 (1-3.25)6 (2-10)0.002*ERO global0 (0-0)0 (0-0)0.59Carpi GS1 (0-2)3 (2-3)0.002*Carpi PD1 (0-2)1 (0-3)0.16MCP GS1 (0-3.25)2 (0-5)0.08MCP PD0 (0-1)1 (0-2)0.03*IPP GS0 (0-1.25)2 (0-3)0.03*IPP PD0 (0-0.25)0 (0-1)0.3MTP GS0.5 (0-3)2 (0-7)0.08MTP PD0 (0-0)0 (0-1)0.02*Wrist extensors GS0 (0-0)0 (0-1)0.1Wrist extensors PD0 (0-0)0 (0-0)0.01*Fibularis GS0 (0-0)0 (0-0)1Fibularis PD0 (0-0)0 (0-0)0.06*RUE GS5 (2-6.25)7 (5-10)0.01†RUE PD2 (1-3.5)5 (2-7)0.01†* Medians compared by Mann-Whitney U test. Statistical significance at a 95% CI. † Logistic regression analysis. Statistical significance at a 95% CI.There were no significant associations between RF/CCPA positivity or CRP/ERS levels and US findings.Conclusion:Patients with IA without arthritis that progressed to CA had significant higher GS and PD scores, hence showing the utility of US to predict disease progression. A RUE of 8 joints and 3 tendon compartments could be enough to achieve this goal.Disclosure of Interests:Pablo Rodríguez-Merlos: None declared, Diana Peiteado: None declared, Irene Monjo: None declared, Laura Nuño: None declared, Alejandro Villalva: None declared, Marta Novella-Navarro: None declared, Torres Jenny Gabriella: None declared, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Roche, Paula Fortea-Gordo Grant/research support from: BMS, Eugenio de Miguel Grant/research support from: Yes (Abbvie, Novartis, Pfizer), Consultant of: Yes (Abbvie, Novartis, Pfizer), Paid instructor for: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Speakers bureau: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz
Background:CXCR5+PD-1hifollicular helper (Tfh) and CXCR5-PD-1hiperipheral helper (Tph) T cells play an important role in the pathogenesis of Rheumatoid Arthritis (RA) by providing help to autoantibody secreting B cells. Whereas Tfh cells typically dwell in the germinal centers of lymphoid organs, Tph cells accumulate at inflamed tissues. An increased frequency of Tph cells and of circulating counterparts of Tfh cells have been described in the peripheral blood of patients with seropositive RA.Objectives:To examine the effect of treatment escalation using biological agents (TNF blockers or abatacept), on the frequency of circulating Tfh (cTfh) and Tph (cTph) cells in RA.Methods:Peripheral blood was drawn from seropositive RA patients with an incomplete response to csDMARDS (n=29) who initiated biological therapy with TNF blockers (TNFb) (n= 17) or abatacept (n= 12), prescribed based on routine clinical practice. cTfh and cTph cell frequencies were determined by flow cytometry of freshly isolated PBMCs at the basal visit and 6 months after starting treatment escalation. For each patient, an age and gender-matched healthy control (HC) was also studied at both time points (n=29).Results:As compared with HC, active RA patients receiving csDMARDs demonstrated a baseline increased frequency of both cTfh and cTph cells. A significant improvement of disease activity as determined by the DAS28 score (ΔDAS28>2.0) was apparent in all of the patients 6 months after initiating biologicals. At that time point, a significant reduction of the previously elevated cTph cell frequency was observed in both treatment groups. However, cTfh cells remained elevated in patients receiving TNFb notwithstanding a good therapeutic response, whereas subjects receiving abatacept experienced a significant abatement of their cTfh cell frequency. Experimental variation of the cTfh and cTph cell numbers in HC was minimal.Conclusion:Abatacept but not TNFb, are able to bring down cTfh cell numbers in RA. This indicates that costimulation blockade can help attain an immunological remission, whereas TNF neutralization may allow a persistent pathogenic germinal center overactivity. At the same time, treatment with both abatacept and TNF blockers results in a downmodulation of the previouly elevated cTph cell numbers, in parallel with the remitting local joint inflammation.References:[1]Simpson N et al, Arthritis Rheum 2010; Craft J, Nat Rev Rheumatol 2012; Arroyo-Villa I et al., Arthritis Res Ther 2014; Rao DA et al., Nature 2017.Disclosure of Interests:Paula Fortea-Gordo Grant/research support from: BMS, Diana Peiteado: None declared, Alejandro Villalba: None declared, Maria-Jose Santos-Bornez Grant/research support from: BMS, Laura Nuño: None declared, Irene Monjo: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Roche
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