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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.

Objective. To compare the clinical efficacy, effect on serum C-reactive protein (CRP), serum amyloid A (SAA), and plasma interleukin-6 (IL-6) levels, and safety of tenidap with a combination of hydroxychloroquineplus-piroxicam, and piroxicam alone, in the treatment of rheumatoid arthritis (RA) patients.Methods. A double-blind, randomized, multicenter study in which patients with active RA were treated with tenidap 120 mg/day, hydroxychloroquine 400 mglday and piroxicam 20 mglday, or piroxicam alone 20 mglday, for 24 weeks.Results. At weeks 12 and 24, tenidap produced greater improvements than piroxicam based on 5 primary efficacy parameters; this improvement showed statistical significance in 4 of the 5 measures at week 12, and in 3 of the 5 measures at week 24. Clinical improvements in the hydroxychloroquine-plus-piroxicamtreated patients were similar to those seen in patients treated with tenidap. Compared with piroxicam, tenidap was associated with significantly greater reductions in serum CRP concentrations at 4, 12, and 24 weeks, and significantly greater reductions in SAA concentrations at weeks 12 and 24. The decrease in SAA concentrations was also significantly greater at weeks 4 and 24 in the tenidap-treated group than in the hydroxychloroquine-plus-piroxicam-treated group. Significant reductions in plasma IL-6 levels were observed at weeks 4, 12, and 24 within the tenidap group, and at week 24 within the hydroxychloroquine-plus-piroxicam-treated group. The overall occurrence of side effects, including gastrointestinal side effects, was similar in all 3 treatment groups. A small proportion of tenidap-treated

The precipitation of a monoclonal IgG2 crystalline cryoglobulin (WEB) is shown to be highly dependent on temperature and concentration. Below a critical concentration of 0.6 mg/mL there is no cryoprecipitation. The kinetics of the aggregation exhibits a concentration-dependent lag time. This evidence suggests that a nucleation event is important in the precipitation. Circular dichroism (CD) was used to investigate the conformational properties of the protein. At a low concentration (0.12 or 0.15 mg/mL), no detectable spectral changes in the far- and near-UV range were noted between 40 and 3 degrees C. However, at higher concentrations (1.21 mg/mL), a small and rapid CD change was observed in the 250-280-nm region at 3 degrees C. This indicates an intermolecular interaction that precedes the precipitation. Cryoprecipitation of WEB was also shown to be dependent on maintenance of intact interchain disulfide bonds. Only one or two interchain disulfides need be cleaved to abolish cryocrystallization and to significantly diminish the CD change at 3 degrees C. The evidence is consistent with the formation of an initial intermediate that involves interactions near the disulfide bonds in the hinge region of the cryoimmunoglobulin. In this model, cleavage of these disulfides prevents this interaction and abolishes cryoprecipitation.