In rheumatoid arthritis, the disease activity score (DAS) is a composite measure widely used in research and clinical practice to assess disease status and therapeutic response. However, the DAS has limitations, notably a mismatch in some people between the level of disease activity indicated by the score and the extent of objectively assessed inflammation. Recent work has shown that not all DAS28 components are independent predictors of imaging-detected inflammation, and that updated DAS28 definitions that exclude TJC28 and patient global VAS are better associated with inflammation. We propose that the time has come to modify the current DAS to make it more reflective of true inflammation, and consider adding other tools if a more comprehensive evaluation of patient well-being is required.

https://www.tandfonline.com/doi/pdf/10.1080/1744666X.2019.1697679

Time to modify the DAS28 to make it fit for purpose(s) in rheumatoid arthritis

Epidemiology and clinical characteristics of interstitial lung disease in patients with rheumatoid arthritis from the JointMan database

SOMAmer reagents and the SomaScan platform: Chemically modified aptamers and their applications in therapeutics, diagnostics, and proteomics

Studies suggest that the expression of glutamate decarboxylase 1 (GAD1), γ-aminobutyric acid (GABA), and GABA receptors are involved in tumor progression. However, the underlying mechanisms of high expression and potential functions of GAD1 and GABA in oral squamous cell carcinoma (OSCC) are not known. In this study, we found that the expressions of GAD1 and GABA were considerably increased in OSCC samples, which were closely associated with clinical stage and lymph node metastasis. The knockdown of GAD1 expression significantly inhibited the proliferation, migration and invasion abilities of OSCC cells by reducing the expression of GABA-mediated GABAB receptors, which could be reversed by exogenous GABA, but did not cause excessive OSCC cell proliferation. And GABA secreted by OSCC cells promoted M2 macrophage polarization for inhibiting anti-tumor immunity by activating GABBR1/ERK/Ca2+. In addition, GABA/GABABR promoted the proliferation and progression of OSCC xenograft tumor. Altogether, our results showed that GAD1 synthetized GABA to promote the malignant progression of OSCC and limits the anti-tumor immunity of macrophages, thereby targeting GABA can be a novel strategy for treating OSCC. 

GAD1-mediated GABA elicits aggressive characteristics of human oral cancer cells

C-reactive protein (CRP) is an inflammatory biomarker with associated clinical utility in a wide number of inflammatory disorders, including rheumatoid arthritis (RA). The interaction of CRP with pro-inflammatory cytokines has been explored before, however its role in complement regulation is more subtle, where CRP is capable of both up and downregulating the complement cascade. CRP is produced in a pentameric form and can dissociate to a monomeric form in circulation which has significant implications for its ability to interact with receptors and binding partners. This dichotomy of CRP structure could have relevance in patients with RA who have significant dysfunction in their complement cascade and also widely varying CRP levels including at the time of flare. This review aims to bring together current knowledge of CRP in its various forms, its effects on complement function and how this could influence pathology in the context of RA. 

A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis

Various aspects of the in vitro culture conditions can impact the functional response of immune cells. For example, it was shown that a Ca2+ concentration of at least 1.5 mM during in vitro stimulation is needed for optimal cytokine production by conventional αβ T cells. Here we extend these findings by showing that also unconventional T cells (invariant Natural Killer T cells, mucosal-associated invariant T cells, γδ T cells), as well as B cells, show an increased cytokine response following in vitro stimulation in the presence of elevated Ca2+ concentrations. This effect appeared more pronounced with mouse than with human lymphoid cells and did not influence their survival. A similarly increased cytokine response due to elevated Ca2+ levels was observed with primary human monocytes. In contrast, primary human monocyte-derived macrophages, either unpolarized (M0) or polarized into M1 or M2 macrophages, displayed increased cell death in the presence of elevated Ca2+ concentrations. Furthermore, elevated Ca2+ concentrations promoted phenotypic M1 differentiation by increasing M1 markers on M1 and M2 macrophages and decreasing M2 markers on M2 macrophages. However, the cytokine production of macrophages, again in contrast to the lymphoid cells, was unaltered by the Ca2+ concentration. In summary, our data demonstrate that the Ca2+ concentration during in vitro cultures is an important variable to be considered for functional experiments and that elevated Ca2+ levels can boost cytokine production by both mouse and human lymphoid cells.

/pdf/the-ca2-concentration-impacts-the-cytokine-production-of-310mk0v6.pdf

The Ca2+ concentration impacts the cytokine production of mouse and human lymphoid cells and the polarization of human macrophages in vitro

Objective A subset of patients with seropositive rheumatoid arthritis (RA) do not mount a C-reactive protein (CRP) response during flares. We hypothesize that these patients are more likely to experience poor clinical care and less likely to respond to traditional therapy. This study questioned whether this presentation was associated with worse disease outcome and distinct immunological features. Methods Using Power Doppler ultrasound, 48 RA patients with active synovitis were recruited; 30 had normal (n)CRP (5 mg/L or less) and 18 had high (h)CRP (more than 5 mg/L) levels. All had equivalent disease burden assessed by other clinical and laboratory parameters. Results Time to diagnosis and time to first disease-modifying antirheumatic drug were significantly longer in nCRP compared with hCRP patients (P < 0.05). Significantly more nCRP patients needed escalation to biologics after 2-year follow-up (P = 0.01). The inflammatory milieu was also different between the two subgroups. Synergy between inflammatory cytokines observed in hCRP patients was lost in nCRP patients, and nCRP patients had significantly increased regulatory T-cell (Treg) frequencies that correlated positively with predictors of poor disease outcome. Conversely, hCRP but not nCRP patients demonstrated a significant upregulation of alternative complement pathway factors that correlated negatively with Treg frequency. Conclusion Patients with nCRP during flares of RA had an altered immunological profile compared with hCRP patients and experienced diagnostic delays and responded less favorably to conventional treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr2.1021

Characterization of a Subset of Patients With Rheumatoid Arthritis for Whom Current Management Strategies are Inadequate.

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The Ca2+ concentration impacts the cytokine production of mouse and human lymphoid cells and the polarization of human macrophages in vitro

Characterization of a Subset of Patients With Rheumatoid Arthritis for Whom Current Management Strategies are Inadequate.