Prevalence of psoriatic arthritis patients achieving minimal disease activity in real-world studies and randomized clinical trials: systematic review with metaanalysis

Objective. To estimate the frequency of patients with psoriatic arthritis (PsA) achieving minimal disease activity (MDA) status in real-world studies and randomized controlled trials (RCT). Methods. A systematic literature search for 2009–2017 was performed in PubMed, Embase, Cochrane Library, and LILACS. Study selection and data extraction were performed by 2 independent researchers. Random-effects single-arm metaanalyses were performed and heterogeneity was assessed using I2. Results. A total of 405 records were identified and 45 studies were analyzed: 39 (86.7%) observational studies and 6 (13.3%) RCT; they included 12,469 patients. The overall prevalence of MDA in cross-sectional studies was 35% (95% CI 30%–41%, I2 = 94%), varying from 17% (95% CI 7%–34%) in patients taking synthetic disease-modifying antirheumatic drugs (DMARD) to 57% (95% CI 41%–71%) in those taking biological DMARD. Prevalence of MDA in cohort studies increased with longer followup time, ranging from 25% (95% CI 15%–40%) with 3- to 4-month followup to 42% (95% CI 38%–45%) with > 24-month followup. Patients with PsA receiving biological DMARD in a real-world context and RCT had similar prevalence of MDA at 6-month followup: 30% (95% CI 21%–41%, I2 = 85%) versus 32% (95% CI 26%–39%, I2 = 79%), respectively. Conclusion. Patients with PsA included in real-world studies had similar prevalence of MDA compared to those in controlled clinical trials. This finding suggests that MDA is a useful treatment target for PsA in the real-world setting.</p

Tumour necrosis factor (TNF) production by T cell receptor-primed T lymphocytes is a target for low dose methotrexate in rheumatoid arthritis

Methotrexate (MTX) is an effective immunosuppressive agent in various chronic inflammatory diseases such as rheumatoid arthritis (RA). However, its mechanisms of action are only partially understood. In this study, we assessed the effects of MTX on the differentiation of peripheral blood (PB) CD4+CD45RA ‘naive’ and CD4+CD45RO ‘memory’ T cells from healthy controls and patients with RA. Accordingly, purified T cells were primed and restimulated in vitro via the T cell receptor (TCR) in the presence of IL-2 to generate effector T cells secreting large amounts of Th1 and Th2 cytokines. We observed that low doses of MTX strongly suppress TNF and to a lesser extent interferon-gamma (IFN-γ) production by T cells from both healthy donors and RA patients when present during T cell priming via the TCR. Similar data were obtained for TCR-primed synovial fluid mononuclear cells in RA. In contrast, production of IL-4 by TCR-primed CD45RA T cells was significantly increased upon MTX treatment. Interestingly, MTX did not enhance IL-4 production when present during restimulation of effector CD45RO T cells, although it still suppressed TNF production. The results indicate that MTX effects depend on the stage of T cell activation and identify TNF production by TCR-primed T lymphocytes as a target for low-dose MTX treatment in RA. These findings could explain the delayed clinical effects of MTX and may contribute to its potent anti-inflammatory and immunoregulatory properties

Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T-cell migration

MUC1 is a transmembrane mucin that is expressed on ductal epithelial cells and epithelial malignancies and has been proposed as a target antigen for immunotherapy. The expression of MUC1 has recently been reported on T and B cells. In this study we demonstrate that following activation in vivo or activation by different stimuli in vitro, human T cells expressed MUC1 at the cell surface. However, the level of expression in activated human T cells was significantly lower than that seen on normal epithelial cells or on breast cancer cells. In contrast, resting T cells did not bind MUC1-specific monoclonal antibodies (mAbs), nor was MUC1 mRNA detectable by reverse transcription–polymerase chain reaction (RT–PCR) or Northern blot analysis in these cells. The profile of activated T-cell reactivity with different MUC1-specific antibodies suggested that the glycoform of MUC1 expressed by the activated T cells carried core 2-based O-glycans, as opposed to the core 1 structures that dominate in the cancer-associated mucin. Confocal microscopy revealed that MUC1 was uniformly distributed on the surface of activated T cells. However, when the cells were polarized in response to a migratory chemokine, MUC1 was found on the leading edge rather than on the uropod, where other large mucin-like molecules on T cells are trafficked. The concentration of MUC1 at the leading edge of polarized activated human T cells suggests that MUC1 could be involved in early interactions between T cells and endothelial cells at inflammatory sites

Enteropathic arthritis in Brazil: data from the Brazilian registry of spondyloarthritis

Inflammatory bowel diseases (Crohn's disease and ulcerative rectocolitis) have extraintestinal manifestations 25% of the patients, with the most common one being the enteropathic arthritis. Methods: Prospective, observational, multicenter study with patients from 29 reference centers participating in the Brazilian Registry of Spondyloarthritis (RBE), which incorporates the RESPONDIA (Ibero-American Registry of Spondyloarthritis) group. Demographic and clinical data were collected from 1472 patients and standardized questionnaires for the assessment of axial mobility, quality of life, enthesitic involvement, disease activity and functional capacity were applied. Laboratory and radiographic examinations were performed. The aim of this study is to compare the clinical, epidemiological, genetic, imaging, treatment and prognosis characteristics of patients with enteropathic arthritis with other types of spondyloarthritis in a large Brazilian cohort. Results: A total of 3.2% of patients were classified as having enteroarthritis, 2.5% had spondylitis and 0.7%, arthritis (peripheral predominance). The subgroup of individuals with enteroarthritis had a higher prevalence in women (P < 0.001), lower incidence of inflammatory axial pain (P < 0.001) and enthesitis (P = 0.004). HLA-B27 was less frequent in the group with enteroarthritis (P = 0.001), even when considering only those with the pure axial form. There was a lower prevalence of radiographic sacroiliitis (P = 0.009) and lower radiographic score (BASRI) (P = 0.006) when compared to patients with other types of spondyloarthritis. They also used more corticosteroids (P < 0.001) and sulfasalazine (P < 0.001) and less nonsteroidal anti-inflammatory drugs (P < 0.001) and methotrexate (P = 0.001). Conclusion: There were differences between patients with enteroarthritis and other types of spondyloarthritis, especially higher prevalence of females, lower frequency of HLA-B27, associated with less severe axial involvement. (C) 2013 Elsevier Editora Ltda. All rights reserved.536452459Wyeth/Pfizer BrazilFederico Foundatio

Increased activation-induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action

Recently, we have described a soluble survival signal for activated lymphocytes from CD14(+) cells. As a result of the importance of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for CD14(+) cells in supporting the outgrowth of autoreactive lymphocytes in RA. To address this issue further, supernatants from activated CD14(+) cells (CD14 cocktails) in both normal controls and RA patients were collected. The relative strength of the CD14 cocktails from normal controls and RA patients was compared. The data showed that depletion of CD14(+) cells resulted in a much higher increase of activation-induced cell death (AICD) and a decrease of lymphocyte proliferation in the peripheral blood mononuclear cells of RA patients compared to normal controls. Interestingly, CD14 cocktails from RA patients provide much stronger protection against AICD compared to those from normal controls. The observed soluble survival signal from CD14(+) cells is a general phenomenon because CD14 cocktails prevent both phytohaemagglutinin A-p- and anti-CD3-induced AICD. Furthermore, supernatants collected from human dendritic cell cultures also prevent activated lymphocytes from undergoing AICD. The data implicate an important role of the CD14(+) cell and its secreted form of survival signal in the pathogenesis of RA

In vitro differentiation of peripheral blood T cells towards a type 2 phenotype is impaired in rheumatoid arthritis (RA)

We have examined the capacity of peripheral blood T cells from RA patients to be polarized in vitro towards a type 1 (T1) or a type 2 (T2) phenotype. Peripheral blood T cells from RA patients and from healthy donors were primed by 1 week of culture with soluble OKT3 in the presence of polarizing cytokines. The recovered T cells were restimulated and their cytokine secretion profile determined. Priming of T cells from RA patients in the presence of recombinant (r)IL-2 plus rIL-12 induced a shift towards a T1 pattern, characterized by increased production of interferon-gamma, that was more pronounced than in the case of healthy donors. Conversely, priming of T cells from RA patients in the presence of IL-4 failed to induce a shift towards a T2 profile after 1 week, whereas it induced T cells from healthy donors to acquire such a profile characterized by heightened production of IL-4, IL-5 and IL-13. However, a T2 polarization profile emerged in T cells from RA patients that were primed in the presence of rIL-4 and subsequently maintained in culture in rIL-2 alone for 1 or 2 additional weeks. We conclude that in vitro differentiation of peripheral T cells towards a type 2 phenotype is impaired in RA. Nevertheless, conditions required to drive peripheral T cells towards a type 2 phenotype were established. Administration of autologous polyclonal T cells expressing a type 2 cytokine secretion profile is proposed as a therapeutic strategy in RA