Adverse events of anti-tumor necrosis factor α therapy in ankylosing spondylitis.

This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α) blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS).The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers.Short-term adverse events occurred in 20.15% (81/402), including rash (3.5%; 14/402), pruritus (1.2%; 5/402), nausea (2.2%; 9/402), headache (0.7%; 3/402), skin allergies (4.0%; 16/402), fever (0.5%; 2/402), palpitations (3.0%; 12/402), dyspnea (0.5%; 2/402), chest pain (0.2%; 1/402), [corrected] abdominal pain (1.0%; 4/402), hypertension (2.2%; 9/402), papilledema (0.5%; 2/402), laryngeal edema (0.2%; 1/402) and premature ventricular contraction (0.2%; 1/402). Long-term adverse events occurred in 59 (34.3%; 59/172) patients, including pneumonia (7.6%; 13/172), urinary tract infections (9.9%; 17/172), otitis media (4.7%; 8/172), tuberculosis are (3.5%; 6/172) [corrected], abscess (1.2%; 2/172), oral candidiasis (0.6%; 1/172), elevation of transaminase (1.7%; 3/172), anemia (1.2%; 2/172), hematuresis (0.6%; 1/172), constipation (2.3%; 4/172), weight loss (0.6%; 1/172), exfoliative dermatitis (0.6%; 1/172). CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05). Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01).This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with anti-TNF-α therapy. Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc

Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane.

Glioblastoma is the most common primary tumor of the brain and has few long-term survivors. The local and systemic immunosuppressive environment created by glioblastoma allows it to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of this immunosuppression. Understanding mechanisms of MDSC formation and function are key to developing effective immunotherapies. In this study, we developed a novel model to reliably generate human MDSCs from healthy-donor CD14+ monocytes by culture in human glioma-conditioned media. Monocytic MDSC frequency was assessed by flow cytometry and confocal microscopy. The resulting MDSCs robustly inhibited T cell proliferation. A cytokine array identified multiple components of the GCM potentially contributing to MDSC generation, including Monocyte Chemoattractive Protein-1, interleukin-6, interleukin-8, and Macrophage Migration Inhibitory Factor (MIF). Of these, Macrophage Migration Inhibitory Factor is a particularly attractive therapeutic target as sulforaphane, a naturally occurring MIF inhibitor derived from broccoli sprouts, has excellent oral bioavailability. Sulforaphane inhibits the transformation of normal monocytes to MDSCs by glioma-conditioned media in vitro at pharmacologically relevant concentrations that are non-toxic to normal leukocytes. This is associated with a corresponding increase in mature dendritic cells. Interestingly, sulforaphane treatment had similar pro-inflammatory effects on normal monocytes in fresh media but specifically increased immature dendritic cells. Thus, we have used a simple in vitro model system to identify a novel contributor to glioblastoma immunosuppression for which a natural inhibitor exists that increases mature dendritic cell development at the expense of myeloid-derived suppressor cells when normal monocytes are exposed to glioma conditioned media

Baseline characteristics of patients experiencing short-term adverse events.

<p>CRP = C-reactive protein. ESR = erythrocyte sedimentation rate. Axial phenotype is ankylosing spondylitis which initially predominantly affects the spine and pelvic joints.</p><p>Baseline characteristics of patients experiencing short-term adverse events.</p

Baseline characteristics of patients experiencing long-term adverse events

<p>CRP = C-reactive protein. ESR = erythrocyte sedimentation rate. Axial phenotype is ankylosing spondylitis which initially predominantly affects the spine and pelvic joints.</p><p>Baseline characteristics of patients experiencing long-term adverse events</p

Comparison of long-term adverse events.

<p>Comparison of long-term adverse events.</p

SFN decreases immunosuppressive MDSC formation in response to GCM but increases CD14-/HLA-DR+ cells.

<p>All experiments performed under hypoxic (1% O₂) conditions. A) Representative dot plots showing CD14/HLA-DR expression in CD14+ monocytes cultured alone or in the presence of BT114 GCM +/- SFN. Monocytes cultured alone are largely CD14+/HLA-DR+ with relatively few mMDSC’s (CD14+/HLA-DR-; 4.75%) (top left). Exposure to BT114 GCM causes a marked increase in mMDSC’s (CD14+/HLA-DR-; 71.3%) (top right). Addition of SFN is associated with a dose-dendent reduction in mMDSC’s (5uM SFN = 42.5% mMDSC’s; 10uM SFN = 5.2% mMDSC’s) (bottom left and right; percent shown in red). Interestingly, this reduction in mMDSC’s is associated with an increase in CD14-/HLA-DR+ cells (percent shown in blue). B) SFN dose-dependent reductions in CD14+/HLA-DR- MDSCs in response to three different GCM’s were seen across monocytes from two unique healthy donors. C) Representative histograms showing immunosuppressive PD-L1 expression in monocytes exposed to BT116 GCM that decreases in a dose-dependent fashion with addition of SFN. D) Bar graph showing median fluorescence intensity of PD-L1 expression in monocytes from three donors exposed to BT116 GCM +/- SFN. E) Bar graph showing increasing population of CD14- / HLA-DR+ cells after SFN exposure among CD14+ cells cultured in GCM (from same experiments as 5A-B). * P < 0.05, ** = P< 0.01,**** = P<0.0001.</p

SFN promotes dendritic cell development from monocytes in both fresh media and GCM.

<p>All experiments performed under hypoxic (1% O₂) conditions. A) Representative dot plots showing CD14 and HLA-DR expression in CD14+ monocytes cultured in fresh media (DMEM) or BT116 GCM +/- SFN. Note that in addition to reductions in CD14+/HLA-DR- mMDSC’s (percent shown in red), there is a SFN-dependent increase in CD14- / HLA-DR+ cells suggestive of dendritic cells (percent shown in blue) in both fresh media and to a lesser extent in GCM. B) Representative dot plots showing CD14, HLA-DR, CD80, and CD83 expression in CD14+ monocytes cultured in DMEM +/- SFN. C) Representative dot plots showing CD14, HLA-DR, CD80, and CD83 epxression in CD14+ monocytes cultured in BT116 GCM +/- SFN. D) Bar graphs showing mean frequency of immature dendritic cells (CD14-/HLA-DR+/CD80+/CD83-) after culturing CD14+ monocytes from three donors in fresh media (DMEM) or BT116 GCM +/- SFN. Note that there is a SFN dose-dependent increase in immature dendritic cells with fresh media. E) Bar graphs showing mean frequency of mature dendritic cells (CD14-/HLA-DR+/CD80+/CD83+) after culturing CD14+ monocytes from three donors in fresh media (DMEM) or BT116 GCM +/- SFN. Note that there is a SFN dose-dependent increase in mature dendritic cells with GCM. n.s. = not significant, ** = P<0.01, *** = P<0.001.</p