No abstract

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599.

ObjectiveTofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers.MethodsThis was a phase I open‐label mechanism‐of‐action study. Cholesterol and lipoprotein kinetics were assessed with 13C‐cholesterol and 13C‐leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks.ResultsLevels of high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A‐I (Apo A‐I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33). In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL‐associated Apo A‐I fractional catabolic rate, or LDL‐associated Apo B fractional catabolic rate. Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased. The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol. Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved.ConclusionThis is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers. The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism. Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.

Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving tofacitinib and atorvastatin. (Pfizer protocol A3921109).

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

BackgroundThe prognostic value of Ki-67 expression in colorectal cancer patients was controversial. Therefore, this meta analysis was conducted to ascertain the prognostic value of Ki-67 expression in colorectal cancer patients.MethodsThe electronic databases, including EMBASE, PubMed, Cochrane Library and Web of Knowledge database, were searched from January 1970 to July 2017. The pooled hazard ratios and 95% confidence intervals were calculated to evaluate the prognostic value of Ki-67 expression for colorectal cancer patients.ResultsTotally 34 eligible studies and 6180 colorectal cancer patients were included in the present meta analysis. The pooled hazard ratios were 1.54(95% CI 1.17–2.02, P = 0.005) for overall survival and 1.43(1.12–1.83, P = 0.008) for disease free survival in univariate analysis. After adjustment of other prognostic factors, the pooled HR was 1.50(95% CI 1.02–2.22, P = 0.03) for overall survival in multivariate analysis.ConclusionThe present meta analysis demonstrated that high Ki-67 expression is significantly correlated with poor overall survival and disease free survival, indicating that high Ki-67 expression may serve as a valuable predictive method for poor prognosis of colorectal cancer patients.

BackgroundThe prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients was controversial. This meta-analysis was performed to clarify the prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients.Materials and MethodsSeveral electronic databases were searched for eligible studies. The pooled odds ratio (OR), hazard ratios (HR) and 95% confidence interval(CI) were calculated to explore the prognostic value and clinicopathologic significance of Ki-67 expression for disease free survival and overall survival.ResultsTotally 5600 gastric cancer patients from 29 studies were included in this study. High Ki-67 expression was significantly related with Lauren's classification (OR = 1.70; P = 0.001; 95%CI: 1.40-2.06) and tumor size(OR = 1.54; P = 0.006; 95%CI: 1.14-2.09). However, high Ki-67 expression was not significantly associated with lymph node metastasis (OR = 1.37; P = 0.138; 95% CI: 0.90-2.08), tumor stage (OR = 1.31; P = 0.296; 95% CI: 0.79-2.16) and tumor differentiation (OR = 1.03; P = 0.839; 95% CI: 0.78-1.35). The pooled HRs were 1.87(P = 0.001; 95% CI 1.30-2.69) for disease free survival and 1.23(P = 0.005; 95% CI 1.06-1.42) for overall survival.ConclusionsHigh Ki-67 expression may serve as a predictive biomarker for poor prognosis in gastric cancer patients. Stratification by Ki-67 expression may be a consideration for selection of therapeutic regimen and integrated managements.

BackgroundTofacitinib is an oral JAK inhibitor for the treatment of RA. There is no direct comparison of tofacitinib monotherapy vs tofacitinib +MTX in MTX inadequate responders (IR) and limited data comparing tofacitinib (±MTX) vs adalimumab (ADA) +MTX in patients (pts) with RA.ObjectivesTo compare efficacy and safety of tofacitinib monotherapy, tofacitinib+MTX, and ADA+MTX in a head-to-head, non-inferiority trial in MTX-IR pts.MethodsIn this randomised, triple-dummy, active-controlled, 1-year, Phase 3b/4 trial (ORAL Strategy; NCT02187055), pts had active RA (≥4 tender/painful joints on motion and ≥4 swollen joints [28-joint count] at baseline [BL]) inadequately controlled with MTX. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (5 mg mono BID), tofacitinib 5 mg BID +MTX (5 mg BID+MTX) or subcutaneous ADA 40 mg every other week +MTX (ADA+MTX); MTX dose: 15–25 mg/wk. The primary endpoint was ACR50 at Month (Mo) 6. Non-inferiority between treatments was declared if the lower bound of 98.34% two-sided confidence intervals of the difference of ACR50 response at Mo 6 was larger than -13% (based on meta analysis of ADA trials1), and superiority if it was larger than 0%. Other endpoints included: ACR20/50/70 and least-squares mean changes from BL in SDAI, DAS28-4(ESR) and HAQ-DI at Mos 6 and 12. Safety was assessed throughout the trial.Results1146 pts were randomised and treated (5 mg mono BID: n=384; 5 mg BID+MTX: n=376; ADA+MTX: n=386). Demographics and BL disease characteristics were similar across groups. Most pts were female (82.7–83.1%), white (75.9–77.1%), with a mean age of 49.7–50.7 years, median disease duration of 5.4–6.1 years and mean HAQ-DI score of 1.6. Across groups, 80.2–81.6% of pts completed the study. ACR50 response rate at Mo 6 was 38.3% for 5 mg mono BID, 46.0% for 5 mg BID+MTX and 43.8% for ADA+MTX. Non-inferiority was demonstrated for 5 mg BID+MTX vs ADA+MTX (P<0.0001) but not for 5 mg mono BID vs ADA+MTX (P=0.0512) or 5 mg mono BID vs 5 mg BID+MTX (P=0.2101) which, although numerically different, were not statistically different (Figure). Tofacitinib monotherapy achieved the efficacy expected of an effective immunomodulator in this pt population. Secondary efficacy analyses were generally consistent with the primary analysis (Table). Adverse event (AE), serious AE and discontinuation due to AE rates were generally clinically similar across groups, though numerically fewer pts had increased alanine aminotransferase with 5 mg mono BID vs 5 mg BID+MTX or ADA+MTX.ConclusionsTofacitinib 5 mg BID+MTX was as effective as ADA+MTX in MTX-IR pts with RA. However, clinical outcomes of all 3 regimens, including tofacitinib 5 mg BID monotherapy, were comparable. There were no new or unexpected safety issues.References Machado et al. Rev Bras Reumatol 2013;53:419–430. AcknowledgementsThis study was funded by Pfizer Inc. Editorial support provided by D Binks of CMC.Disclosure of InterestR. Fleischmann Grant/research support from: Abbott, Amgen, Astellas, Bristol-Myers Squibb, Boehringer Inge...