Neutrophils Are Essential As A Source Of Il-17 In The Effector Phase Of Arthritis

<div><p>Objective</p><p>Th17 has been shown to have a pivotal role in the development of arthritis. However, the role of IL-17 in the T cell-independent effector phase has not fully been examined. We investigated whether IL-17 is involved in the effector phase of arthritis by using K/BxN serum-induced arthritis model.</p><p>Methods</p><p>K/BxN serum was transferred into IL-17 knockout (KO) mice, SCID mice and their control mice, and arthritis was evaluated over time. In order to clarify the source of IL-17 in the effector phase, neutrophils or CD4+ T cells collected from IL-17 KO or control mice were injected into IL-17 KO recipient mice together with K/BxN serum. To examine if neutrophils secrete IL-17 upon stimulation, neutrophils were stimulated with immune complex in vitro and IL-17 in the supernatant was measured by ELISA.</p><p>Results</p><p>K/BxN serum-induced arthritis was much less severe in IL-17 KO mice than in WT mice. Since K/BxN serum-transferred SCID mice developed severe arthritis with high serum IL-17 concentration, we speculated neutrophils are the responsible player as an IL-17 source. When wild type (WT) but not IL-17 KO neutrophils were co-injected with K/BxN serum into IL-17 KO mice, arthritis was exacerbated, whereas co-injection of WT CD4+ T cells had no effect. In vitro, stimulation of neutrophils with immune complexcaused IL-17 secretion.</p><p>Conclusions</p><p>Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. The trigger of secreting IL-17 from neutrophils may be immune complex.</p></div

Suppressor of TCR signaling-2 (STS-2) suppresses arthritis development in mice

<p><b>Objectives:</b> Suppressor of TCR signaling-2 (STS-2) is one of the RA susceptibility genes identified in genome-wide association studies (GWAS). We tried to verify the involvement of STS-2 on the development of autoimmune arthritis in a mouse model.</p> <p><b>Methods:</b> STS-2 knock-out (KO) and wild type (WT) mice were immunized with chicken type II collagen (CII). For CD4⁺ helper T cell (Th) subset analysis, intracellular cytokines in splenocytes and lymph node cells were stained and analyzed by flow cytometry. Regulatory T cell (Treg) function was analyzed by co-culturing effector CD4⁺T cells and Tregs collected from non-immunized mice.</p> <p><b>Results:</b> CII-immunized STS-2 KO mice developed arthritis more frequently than WT mice. Although the T cell activation profile and Th subset in spleen and LNs were similar between STS-2 KO and WT mice, STS-2 KO mice showed increased IL-2-producing CD4⁺T cells in spleen when compared with WT mice. Accordingly, STS-2 KO CD4⁺T cells promoted IL-2 production by TCR stimulation. However, STS-2 KO Tregs normally suppressed T cell proliferation.</p> <p><b>Conclusion:</b> We proved that STS-2 is involved in the arthritis development by collagen-induced arthritis. Higher IL-2 production from STS-2 KO T cells is suggested to have a main pathogenic role in arthritis development.</p

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study- - Fig 2

<p><b>Drug survival rates due to inefficacy of (a) non-adjusted and (b) adjusted cases.</b> Adjusted confounder s were baseline sex, age, disease duration, DAS28-ESR, HAQ-DI, RF and ACPA positivity, concomitant MTX and PSL dose, presence of concomitant csDMARDs (BUC, IGU, SASP, and TAC), date of starting bDMARDs, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, DAS28-ESR = Disease Activity Score in 28 joints using erythrocyte sedimentation rate, HAQ-DI = Health Assessment Questionnaire disability index, RF = rheumatoid factor, ACPA = anti- cyclic citrullinated peptide antibody, MTX = methotrexate, PSL = prednisolone, csDMARDs = conventional synthetic disease-modifying antirheumatic drugs, BUC = bucillamine, IGU = iguratimod, SASP = salazosulfapyridine, TAC = tacrolimus, bDMARDs = biological disease-modifying antirheumatic drugs.</p

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study- - Fig 3

<p><b>Drug survival rates due to toxic adverse events of (a) non-adjusted and (b) adjusted cases.</b> Adjusted confounder s were baseline sex, age, disease duration, DAS28-ESR, HAQ-DI, RF and ACPA positivity, concomitant MTX and PSL dose, presence of concomitant csDMARDs (BUC, IGU, SASP, and TAC), date of starting bDMARDs, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, DAS28-ESR = Disease Activity Score in 28 joints using erythrocyte sedimentation rate, HAQ-DI = Health Assessment Questionnaire disability index, RF = rheumatoid factor, ACPA = anti- cyclic citrullinated peptide antibody, MTX = methotrexate, PSL = prednisolone, csDMARDs = conventional synthetic disease-modifying antirheumatic drugs, BUC = bucillamine, IGU = iguratimod, SASP = salazosulfapyridine, TAC = tacrolimus, bDMARDs = biological disease-modifying antirheumatic drugs.</p

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study- - Fig 1

<p><b>Overall drug survival rates of (a) non-adjusted and (b) adjusted cases.</b> Adjusted confounder s were baseline sex, age, disease duration, DAS28-ESR, HAQ-DI, RF and ACPA positivity, concomitant MTX and PSL dose, presence of concomitant csDMARDs (BUC, IGU, SASP, and TAC), date of starting bDMARDs, and number of previously used bDMARDs.ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, DAS28-ESR = Disease Activity Score in 28 joints using erythrocyte sedimentation rate, HAQ-DI = Health Assessment Questionnaire disability index, RF = rheumatoid factor, ACPA = anti- cyclic citrullinated peptide antibody, MTX = methotrexate, PSL = prednisolone, csDMARDs = conventional synthetic disease-modifying antirheumatic drugs, BUC = bucillamine, IGU = iguratimod, SASP = salazosulfapyridine, TAC = tacrolimus, bDMARDs = biological disease-modifying antirheumatic drugs.</p

Additional file 2: of Factors associated with the achievement of biological disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: the ANSWER cohort study

Figure S2. Kaplan–Meier survival curve for maintaining bDMARD-free remission after discontinuation of different types of bDMARDs in bDMARD-naïve patients. bDMARD-naïve patients classified into four groups based on types of bDMARDs. Kaplan–Meier method used to estimate BFR maintenance time. bDMARD biological disease-modifying anti-rheumatic drug, BFR biological disease-modifying anti-rheumatic drug-free remission, TNFi(mAb) monoclonal antibodies against TNF (infliximab, adalimumab, and golimumab), TNFi(R/P) soluble TNF receptor or Fab fragments against TNF fused with polyethylene glycol (etanercept and certolizumab), CTLA4-Ig abatacept, IL-6Ri interleukin-6 receptor inhibitor (tocilizumab), CI confidence interval (PDF 80 kb) (PDF 79 kb

Logistic regression analysis of HLA-DRB1 alleles with ACPA-positive RF-positive RA and ACPA-positive RF-negative RA.

*<p><i>p</i>-values and odds ratios in logistic regression analysis using SE and HLA-DRB1*09:01.</p

Direct comparison of HLA-DRB1 allele frequency between ACPA-negative RF-positive RA and ACPA-negative RF-negative RA.

<p>Direct comparison of HLA-DRB1 allele frequency between ACPA-negative RF-positive RA and ACPA-negative RF-negative RA.</p

Summary of the HLA-DRB1 alleles associated with ACPA-negative RA and ACPA-positive RA.

<p>The relationships between the RF-positive and RF-negative subsets of ACPA-negative and ACPA-positive RA in terms of their associations with HLA-DRB1 alleles are illustrated. While the two subsets of ACPA-positive RA seem to share most associations with HLA-DRB1, the two ACPA-negative RA subsets possess specific alleles and HLA-DRB1 diplotypes. The underlined alleles are protective alleles.</p

Association of HLA-DRB1 alleles with ACPA-negative RF-negative RA.

<p>Association of HLA-DRB1 alleles with ACPA-negative RF-negative RA.</p