Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate: results from a phase 3 study.

OBJECTIVES: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy. METHODS: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12. RESULTS: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo. CONCLUSIONS: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.

Unbalanced expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of rheumatoid arthritis.

OBJECTIVE: The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of patients with rheumatoid arthritis. METHODS: Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6+CD4+T, CD4+CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. RESULTS: The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23±10.71)% vs. (18.83±7.32)%, p<0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71±1.63) vs. (2.00±1.27), p=0.002; (2.62±2.08) vs. (0.62±0.29), p<0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90 (6.10±80.10)% vs. (52.49±19.18)%, p<0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49±19.18)% vs. (23.18±5.62)% vs. (18.06±7.80)%, X2=24.03, p<0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs [(46.02±14.68)% vs. 17.90 (6.10±80.10)% vs. (34.22±10.33)%, X2=38.29, p<0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+CD25+T cells. CONCLUSION: AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood.

Unbalanced expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of rheumatoid arthritis / Expressão não equilibrada do receptor de hidrocarboneto arílico nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ do sangue periférico na artrite reumatoide

ABSTRACT Objective: The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of patients with rheumatoid arthritis. Methods: Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6+CD4+T, CD4+CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. Results: The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23 ± 10.71)% vs. (18.83 ± 7.32)%, p < 0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71 ± 1.63) vs. (2.00 ± 1.27), p = 0.002; (2.62 ± 2.08) vs. (0.62 ± 0.29), p < 0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90 (6.10 ± 80.10)% vs. (52.49 ± 19.18)%, p < 0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49 ± 19.18)% vs. (23.18 ± 5.62)% vs. (18.06 ± 7.80)%, X 2 = 24.03, p < 0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs [(46.02 ± 14.68)% vs. 17.90 (6.10 ± 80.10)% vs. (34.22 ± 10.33)%, X 2 = 38.29, p < 0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+CD25+T cells. Conclusion: AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood.

RESUMO Objetivo: Analisar o papel do receptor de hidrocarboneto arílico (AhR) nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ no sangue periférico de pacientes com artrite reumatoide (AR). Métodos: Foi aplicada citometria de fluxo para determinar a proporção de células AhR positivas em linfócitos CCR6+ CD4+ e CD4+ CD25+ do sangue periférico e células mononucleares periféricas de cada indivíduo. Os níveis de expressão relativa de ácido ribonucleico mensageiro (do inglês ribonucleic acid, RNAm,) de AhR e RNAm de enzima de primeiro estágio essencial para o AhR (CYP1A1) foram testados por reação em cadeia de polimerase (do inglês polymerase chain reaction, PCR,) em tempo real. Resultados: A percentagem de células AhR positivas nas células mononucleares do sangue periférico foi maior no grupo com AR do que nos indivíduos saudáveis [(35,23 ± 10,71)% vs. (18,83 ± 7,32)%, (p < 0,01)]. Os níveis de expressão de AhR e CYP1A1 estavam aumentados em pacientes com AR quando comparados com os controles [(3,71 ± 1,63) vs. (2,00 ± 1,27), p = 0,002; (2,62 ± 2,08) vs. (0,62 ± 0,29), p < 0,01, respectivamente]. Em pacientes com AR, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente inferior à dos controles [17,90 (6,10 ± 80,10)]% vs. (52,49 ± 19,18)%, p < 0,01]; em controles saudáveis, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente mais elevada do que nos linfócitos T CCR6+ CD4+ e também foi significativamente maior do que nas células mononucleares do sangue periférico (do inglês peripheral blood mononuclear cells, PBMC,) [(52,49 ± 19,18)% vs. (23,18 ± 5,62)% vs. (18,06 ± 7,80)%, X 2 = 24,03, p < 0,01]; em pacientes com AR, a percentagem de células AHR positivas nos linfócitos T CCR6+ CD4+ era significativamente maior em comparação com os linfócitos T CD4+ CD25+ e PBMC (46,02 ± 14,68)% vs. [17,90 (6,10 ± 80.10)]% vs. (34,22 ± 10,33)%, X2 = 38,29, p < 0,01]; no entanto, não foi encontrada correlação estatisticamente significativa entre os dados clínicos e células AhR positivas em linfócitos T CCR6+ CD4+ e CD4+ CD25+. Conclusão: O Ahr pode participar do progresso patológico da AR ao controlar a diferenciação de linfócitos Th17 e Treg no sangue periférico.