Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

Peroxisome proliferator-activated receptors α (PPARα) agonists, or fibrates, are used in the treatment for dyslipidemia. Experimental data suggest that fibrates have anti-inflammatory properties, and PPARα is essential for the differentiation of endothelial progenitor cells (EPC) which diminished pool in rheumatoid arthritis (RA) contributes to accelerated atherosclerosis. The data on fibrates' effects in patients with RA are limited. The aim of this study was to investigate changes in disease activity, inflammatory markers, lipid profile, and circulating EPC in active RA patients treated with fenofibrate. Twenty-seven patients with active RA taking traditional disease-modifying antirheumatic drugs (DMARDs) were prescribed fenofibrate (145 mg/day) for 3 months. All patients received background traditional DMARDs in stable doses. The outcomes measured were clinical disease activity variables, circulating cytokines, adipokines, lipids, and EPC. Twenty-five patients completed the study. At the end of treatment, there was a significant reduction in DAS28, all individual DAS28 components except tender joint count, the duration of morning stiffness, and in the patient's assessment of disease activity. Fifteen (60 %) patients achieved good/moderate EULAR response, while 10 (40 %) patients satisfied ACR20 response criteria. Treatment with fenofibrate resulted in significant decrease in CRP and IL-6 concentrations and improvement in lipid profile. There was no change in the concentrations of circulating EPC. In conclusion, fenofibrate treatment is associated with reduced inflammation and improved lipid profile in RA patients. Large randomized controlled studies are needed to confirm these results and to define the role of fibrates in the treatment for RA.

Background Anti-inflammatory and antiatherogenic properties of peroxisome proliferator-activated α (PPARα) receptor agonists (fibrates) suggest their utility in the treatment of various inflammatory rheumatic disorders associated with accelerated atherosclerosis. They include osteoarthritis (OA), particularly its erosive phenotype (EOA) characterized by pronounced synovial inflammation. Putative EOA biomarkers reflecting extent of chronic inflammation and increased risk of atherosclerosis are serum cytokines and adipokines. Another candidate biomarker for cardiovascular morbidity in OA is number of circulating endothelial progenitor cells (EPC). There have been no published studies evaluating fenofibrate efficacy and its effects on systemic cytokine and adipokine production and EPC concentrations in patients with erosive OA. Objectives To assess the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of EPC in patients with EOA. Methods EOA patients received treatment with 145 mg of fenofibrate per day for 12 weeks. The studied efficacy outcomes were pain levels (100 mm VAS), functional index for hand OA (FIHOA), Cochin index, patient and physician global assessment (100 mm VAS), tender and swollen joint count, duration of morning stiffness, and ESR. Response was assessed in accordance with OMERACT-OARSI criteria. Serum was obtained from each patient and peripheral blood mononuclear cells were isolated on baseline and at week 12 of the treatment. TNF-α, IL-6, IL-1, IL-17, IFN-γ, IL-10, apiponectin and resistin were measured in sera using specific ELISA. Endothelial progenitor cell (EPC) counts in peripheral blood were evaluated by flow cytometry as CD34+/CD144+/CD3- cells within the lymphocyte gate. Results Fifteen patients (all women, median age 61 years, IQR 57-63) were enrolled in the study. Fenofibrate treatment was associated with significant decreases in pain score, TJC, morning stiffness, disease activity score, Cochen index, and ESR (Table). Eight (53%) patients developed OMERACT-OARSI response at the end of treatment. Serum IL-10 concentrations significantly (p=0.03) decreased while no changes in other studied cytokines and adipokines were detected. There were also no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. Table 1. Efficacy parameters at baseline and after the treatment (median and IQR are presented) Week 0Week 12p Pain (100 mm VAS)28 (20-50)20 (10-36)0.0008 TJC8 (5-16)5 (4-8)0.007 SJC7 (3-10)4 (1-7)0.175 Morining stiffness60 (20-130)20 (0-30)0.0035 Disease activity (100 mm VAS)51 (45-60)20 (18-40)<0.0001 Patient’s global assessment (100 mm VAS)50 (38-64)31 (21-43)0.0141 Cochen index8 (4-12)4 (0-14)0.0182 ESR, mm/h21 (7.75-28.5)10.5 (7.25-18.5)0.0195 Conclusions In EOA patients, treatment with fenofibrate is associated with decreased pain, improved hand function and ESR reduction but has no effect on pr...

Background Experimental findings indicate that peroxisome proliferator-activated α (PPARα) receptor agonists (fibrates), apart from their lipid-lowering effects, exhibit anti-inflammatory activity, influence angiogenesis and modulate glucocorticoid effects. Recent data suggest that fibrates may promote the differentiation of endothelial progenitor cells (EPC) which diminished pool in RA is thought to contribute to enhanced atherosclerosis. Thus, this class of drug may be a useful adjunct to the current arsenal of DMARDs. Although there have been no randomized controlled trials, several small reports have shown clinical improvement in RA patients treated with fenofibrate. The influence of fenofibrate on cytokine production and EPC concentrations in vivo in RA patients is unknown Objectives To evaluate changes in disease activity, circulating cytokine concentrations and levels of EPC in RA patients following treatment with fenofibrate. Methods Patients with active (DAS28 >3.2) RA received treatment with 145 mg of micronised fenofibrate per day for 12 weeks. Clinical efficacy outcomes recorded were: DAS28, individual DAS28 components, ACR responses, HAQ, pain levels (VAS), and ESR. TNF-α, IL-6, IL-1, IL-17, IFN-γ, and IL-10 concentrations were measured in sera using specific ELISA. EPC counts in peripheral blood were evaluated by flow cytometry as CD34+/CD144+/CD3- cells within the lymphocyte gate. Analysis was performed using Friedman’s test for clinical variables and ESR and using Wilcoxon matched pairs test for laboratory parameters. Results Twenty four patients (21 women, three men, median age 60.6 years, IQR 52.1- 65.5) were enrolled in the study. Median disease duration was 7.64 (IQR 2.35-17) years. All subjects had been taking methotrexate in stable dose of 13.75 mg/w (IQR 10-15) for at least 3 months prior to the study. At the end of treatment there were significant improvements in DAS28, swollen joint count, general health (VAS), patient and physician global assessment of disease activity (VAS), and morning stiffness (Table). Thirteen (59%), five (22.7%), and one (4.3%) patients developed ACR20, ACR50, and ACR70 responses, respectively. One patient achieved clinical remission (DAS28<2.6). Fenofibrate treatment was associated with significant decrease in serum IL-6 (p=0.04) and IL-10 (p=0.03). Whereas baseline EPC concentrations were lower in RA than in 15 control OA patients (0.17% and 0.3%, p=0.036), no significant changes were observed in circulating EPC levels after fenofibrate treatment (p=0.36). Two patients terminated the study prematurely due to severe acute sciatica and were not included in the analysis. No patient experienced disease flare during the study period. Table 1. Clinical efficacy parameters at baseline and at the end of treatment (median and IQR are presented) Week 0Week 12p DAS286.36 (5.98-6.78)4.73 (3.85-5.64)<0.0001 SJC7 (5–0)3 (1-4)<0.0001 TJC17 (13–20)14 (3–20)0.0563 General health, mm53 (44–70)38.5 (25–54)0.0001 ESR, mm/h35.5 (32–50)14.5 (10–30)<0.0001 Activity by patient, mm57 (...

Background Statins have been demonstrated to reduce disease activity in rheumatoid arthritis (RA) patients. There is growing evidence that another class of hypolipidemic drugs – PPARalpha agonists, or fibrates, may play a role in the treatment of RA. There is a lack of data on comparative effects of statins and fibrates in RA. Objectives To evaluate comparative anti-inflammatory effects of fenofibrate and simvastatin in patients with active RA. Methods We retrospectively compared clinical efficacy of fenofibrate and simvastatin in similar groups of patients with active RA who had participated in two respective open-label before-after clinical trials performed in a single center. The main eligibility criteria were fulfillment of ACR criteria and DAS28 > 3.2. Each group consisted of 33 patients. Patients received treatment with 145 mg of micronised fenofibrate or 40 mg simvastatin per day for 12 weeks. Evaluations were made at baseline and at weeks 4, 8 and 12. Clinical efficacy outcomes recorded were: DAS28, individual DAS28 components, ACR responses, HAQ, pain levels (VAS), and ESR. Longitudinal changes in clinical efficacy parameters were compared between groups using generalized estimating equations (GEE). The models were adjusted for baseline patients’ age, disease duration, concomitant disease modifying antirheumatic drugs use, and baseline disease activity. Results The mean duration of disease was 8.2 (IQR 2.4,19) years and 9 (IQR 6,13) years in fenofibrate and simvastatin groups, respectively. The fenofibrate group had slightly lower baseline disease activity (6.3 (SD 0.8) vs 6.8 (SD 0.8), p=0.009). Moderate EULAR response was achieved in 17 (51.5% ) patients receiving fenofibrate and 11 (33.3)% patients who were prescribed simvastatin. Using GEE analysis, fenofibrate treatment was shown to be associated with a greater reduction in DAS28, swollen joint count, and patient’s assessment of general health. There was also a trend towards improvement in ESR in fenofibrate group (Table). Conclusions The results of this retrospective analysis suggest that in active RA patients fenofibrate may have more pronounced anti-inflammatory effects that simvastatin. These findings have to be confirmed in a randomized study. Disclosure of Interest None Declared