Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BACKGROUND: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. OBJECTIVE: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE). METHODS: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count. RESULTS: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]). CONCLUSION AND CLINICAL RELEVANCE: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

Different effect of oral cyclosporine therapy and oral antihistamine therapy on serum high-sensitivity C-reactive protein level and thymus and activation-regulated chemokine level in atopic dermatitis in older children and adulthood.

BACKGROUND: Many patients with atopic dermatitis (AD) are treated with oral cyclosporine or antihistamine therapy in clinical practice. OBJECTIVE: To evaluate the effectiveness of oral cyclosporine and antihistamine therapy on clinical and laboratory findings in patients with AD. SUBJECTS AND METHODS: Twenty-five patients with AD (male-female = 11 : 14, age 16-42 years old, mean 26.2 years old) were treated with oral cyclosporine therapy. Twenty-three patients with AD (male-female = 10 : 13, age 15-32 years old, mean 24.2 years old) were treated with oral antihistamine therapy. Laboratory findings including high-sensitivity C-reactive protein (CRP) and thymus and activation-regulated chemokine (TARC) were statistically studied. RESULTS: Serum TARC level after oral cyclosporine therapy (1013 ± 883 pg/ml) was significantly decreased compared to before therapy (38 194 ± 4678 pg/ml; P < 0.02). Basophil counts in peripheral blood after the therapy (49.7 ± 26.4 × 10(-3) cells/µl) were more significantly increased than before therapy (41.1 ± 16.7 × 10(-3) cells/µl; P < 0.05). Serum high-sensitivity CRP level after antihistamine therapy (0.09 ± 0.08 mg/ml) was significantly decreased compared to before therapy (0.13 ± 0.12 mg/ml; P < 0.05). Basophil counts in peripheral blood after the therapy (33.4 ± 16.2 × 10(-3) cells/µl) were more significantly decreased than before therapy (41.5 ± 23.3 × 10(-3) cells/µl; P < 0.01). CONCLUSION: Different effects of oral cyclosporine therapy and oral antihistamine therapy to serum high-sensitivity CRP level, TARC level, and peripheral blood basophils in adult patients with AD were shown. A combination of these two therapies may be more effective for the treatment of AD in adults.

The effects of PG102, a water-soluble extract from Actinidia arguta, on serum total IgE levels: a double-blind, randomized, placebo-controlled exploratory clinical study.

BACKGROUND: Recent studies have reported that blocking IgE has a potentially beneficial role in the treatment of various allergic diseases. Previously, we found that PG102, a water-soluble extract prepared from the edible fruits of Actinidia arguta, can effectively reduce IgE levels using murine models. AIMS: To evaluate the efficacy of PG102 at lowering levels of total IgE in asymptomatic subjects with atopy. METHODS: A total of 90 asymptomatic subjects with atopy were randomized equally to a PG102 group or a placebo control group and treated for 8 weeks in a double-blind manner. Total serum IgE, eosinophilic cation protein (ECP), eotaxin, thymus, and activation-regulated chemokine (TARC), IL-4, IL-5, and IL-13 levels were measured. Eosinophil counts were determined before and after treatment, and results were compared. In addition, possible adverse reactions were thoroughly checked in this first human trial. RESULTS: Levels of total IgE significantly increased in the control group but showed no change in the PG102 group, and change differences between the control and PG102 groups were significant (+12.9%, vs.-5.7%, p = 0.015). Levels of ECP and eotaxin and eosinophil counts produced similar results. However, the other variables showed no significant changes after treatment. CONCLUSION: In this exploratory clinical trial, it was found that 8 weeks of treatment with PG102 effectively reduced the levels of total IgE in apparently asymptomatic subjects with atopy.

CC chemokine ligand 17 in periodontal diseases: expression in diseased tissues and production by human gingival fibroblasts.

BACKGROUND AND OBJECTIVE: It has been reported that T helper 2 (Th2) cells are related to exacerbation of periodontal disease. However, it is uncertain how the migration of Th2 cells is controlled. In this study, we examined the expression of CC chemokine ligand 17 (CCL17), which is a Th2 chemokine, in periodontal tissues. Moreover, we investigated the effects of cytokines and toll-like receptor (TLR) ligands on the production of CCL17 by human gingival fibroblasts (HGFs). MATERIAL AND METHODS: We used immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to detect CCL17 in periodontal tissues. HGFs were exposed to cytokines and TLR ligands. Expression of CCL17 was examined by RT-PCR and enzyme-linked immunosorbent assay. We used signal transduction inhibitors in some experiments. RESULTS: Both CCL17 and its receptor, CC chemokine receptor 4 (CCR4), were expressed in diseased periodontal tissues. A combination of tumour necrosis factor alpha (TNF-alpha) and interleukin (IL)-4/IL-13 increased CCL17 expression. Moreover, treatment of HGFs with a low dose of interferon-gamma (IFN-gamma) in combination with TNF-alpha and IL-4 or IL-13 had synergistic effects on the production of CCL17, whereas a high dose of IFN-gamma inhibited CCL17 production. Furthermore, Escherichia coli (E. coli) lipopolysaccharide (TLR4 ligand) and Pam3CSK4 (TLR2 ligand) inhibited CCL17 production by TNF-alpha + IL-4-stimulated HGFs, while CpG DNA (TLR9 ligand) enhanced TNF-alpha + IL-4 induced-CCL17 production by HGFs. Furthermore, a c-Jun NH2 terminal kinase (JNK) inhibitor, a phosphatidylinositol-3-kinase (PI3K) inhibitor and a nuclear factor kappa B (NF-kappa B) inhibitor inhibited CCL17 production by HGFs. CONCLUSION: These results suggest that the CCL17 produced by HGFs may be involved in the migration of Th2 cells into inflamed tissues, and provide evidence that CCL17 production is controlled by cytokines and TLR ligands in periodontal disease.

Differential suppression of dendritic cell cytokine production by anti-inflammatory drugs.

BACKGROUND: Various anti-inflammatory drugs are available for the treatment of skin disorders. In these diseases, untoward immune responses to endogenous and/or environmental antigens are initiated by maturation and polarization of dendritic cells (DC). OBJECTIVE: To explore the suppressive effects of anti-inflammatory drugs on DC maturation and, in particular, polarization. METHODS: Exposure of DC to nickel in vitro results in DC maturation and secretion of both type 1 and type 2 cytokines, thereby providing a model to study the effects of anti-inflammatory drugs on DC responses. The inhibitory effects of anti-inflammatory drugs (ciclosporin, dexamethasone, diclofenac, dimethylfumarate, hydrocortisone, lactoferrin, 1-alpha,25-dihydroxyvitamin D3) on DC maturation (CD83, CD86, HLA-DR, CXCL8) and polarization (type 1: IL-12p70, TNF-alpha; type 2: IL-10, CCL17) were studied. RESULTS: All anti-inflammatory drugs, except for lactoferrin, had inhibitory effects on DC maturation. Hydrocortisone and dexamethasone exclusively suppressed the release of type 1 cytokines. A less pronounced, but similar profile was observed for dimethylfumarate and 1-alpha,25-dihydroxyvitamin D3. Ciclosporin suppressed both type 1 and 2 cytokines. In contrast, diclofenac suppressed only type 2 DC cytokine secretion. CONCLUSION: The present results give more insight into the pharmacological effects of immunosuppressive drugs on the immune system, and can thereby contribute to a more rational selection of anti-inflammatory drugs for the treatment of inflammatory skin disorders.