Discussion
death, pSS [Presentation of antigenic peptide, autoimmune diseases, cardiac arrest, transient decrease
MINOR, DISEASE, AUTOIMMUNE DISEASES, CARDIAC ARREST, SECONDARY
The primary endpoint of this study, defined as the proportion of patients with a ≥3 point reduction in ESSDAI score after 12 weeks’ treatment compared with baseline, was not met. The ESSDAI is a compound clinical scoring system that measures 12 domains which capture disease activity in SS [Although the ESSDAI is widely used to measure disease activity in clinical studies, ensuring an accurate and reproducible rating of each domain remains a challenge [In addition to the ESSDAI and ESSPRI, we also evaluated quality of life scores (SF-36 mental and physical components), unstimulated tear production, and mechanically stimulated salivary flow. The scores for both components of the SF-36 were similar between both study arms at the end of the treatment period. Both groups showed a decline in unstimulated tear production at week 12 compared with baseline; however, the RO5459072 group showed less of a decline compared with the placebo group. At week 12, the RO5459072 arm showed a slight trend towards improvement over the placebo arm with respect to mechanically stimulated salivary flow. However, the results for these secondary endpoints were not statistically significant.Analysis of soluble biomarkers (including cathepsin S mass, cystatin C, 4-β-hydroxycholesterol and BAFF) was performed at baseline and throughout the 12-week treatment period. Over the treatment period, we observed a 2.4-fold increase in the concentration of cathepsin S mass (relative to baseline) in the RO5459072 arm, reaching a plateau at week 2 (Several other exploratory endpoints were measured in this study to assess the effect of RO5459072 on T cell–dependent activation of B cells. We observed a trend towards a modest and transient decrease in the number of B cells in the RO5459072 group (at week 2), and a small decrease in the number of CD8+ T cells at week 12. These observations are consistent with the expected effects of RO5459072 on MHC-II-mediated immune stimulation of adaptive T cells and B cells. No significant trends were observed in histological analyses of minor salivary gland biopsies. Given the lack of a clear signal for these parameters, our findings highlight the need for further studies to fully understand the mechanisms of MHC-II-mediated immune stimulation in pSS.There are several limitations to our study. First, there is no formal consensus on the optimal outcome for evaluating treatment efficacy in pSS. Currently, the ESSDAI and ESSPRI are the only disease-specific validated clinical scores available for pSS [Presentation of antigenic peptide by MHC-II expressed on the surfaces of antigen-presenting cells is central for adaptive immune responses and for autoimmune diseases mediated by CD4+ T cells. Removal of the invariant chain bound to MHC-II is essential for both peptide loading and also for MHC-II to exit the endoplasmic reticulum for subsequent cell surface expression. Removal of the invariant chain is achieved by a number of proteolytic steps, the last being mediated by cathepsin S in B cells and dendritic cells [RO5459072 was well tolerated in our study population, albeit 15.8% of the RO5459072 arm discontinued treatment or withdrew. One death was reported (due to cardiac arrest in a placebo patient). No apparent drug-related trends or signals emerged in terms of AEs, ECG, vital signs and safety laboratory parameters.