ACR Congress Review 2019

At 6 months post-switch, patients switched to adalimumab achieved 69%, 37%, 16% improvements in
ACR20/50/70 responses, and 40% and 21% achieved DAS28-CRP≤3.2 and ≤2.6. Patients switched to
upadacitinib achieved 81%, 56%, 32% improvements in ACR20/50/70, and 56% and 35% achieved
DAS28-CRP≤3.2 and ≤2.6 at 6 months. Mean changes from the original baseline in HAQ-DI were -0.58
and -0.73 for patients switching to adalimumab and upadacitinib, respectively. The proportions of
patients with infection and serious infection through 6 months post-switching appeared consistent with
those observed for adalimumab and upadacitinib during comparable periods. The authors concluded
that patients with initial non-response to either upadacitinib or adalimumab can benefit from switching to
the other therapy [2907*].
Effects of upadacitinib on reverse cholesterol transport
Charles-Schoeman and colleagues presented findings on the effect of upadacitinib treatment on
cholesterol efflux capacity (CEC) and the association of CEC with changes in inflammation and serum
lipids using data from a subset of patients in the BALANCE II and SELECT-NEXT studies. In both
studies, changes in global and ABCA1-dependent CEC, and to a lesser extent non-ABCA1-dependent
CEC, were significantly higher in the upadacitinib-treated group compared with the placebo group. Thus,
upadacitinib treatment was associated with significant improvement in CEC. This effect was observed
even among those demonstrating minimal clinical response (but not in those treated with placebo). The
effect seemed to be primarily driven by ABCA1-dependent cholesterol efflux and is strongly correlated
with a rise in HDL cholesterol as well as reduction in systemic inflammation as measured by change in
CRP levels [510].
Normalisation of key pathobiological pathways in upadacitinib-treated patients
A poster on the mode of action of upadacitinib in patients with RA was presented by Sornasse et al. The
authors used a proteomic approach to evaluate a set of plasma proteins associated with inflammation in
randomly selected plasma samples from patients in the SELECT-NEXT and SELECT-BEYOND studies
(placebo, n=167; upadacitinib 15 mg QD, n=200). Consistent with its selectivity for JAK1, upadacitinib
was found to operate via inhibition of multiple JAK1-dependent upstream pathways that result in the
normalisation of key functional downstream effects associated with the pathobiology of RA, including
T cell and myeloid cell-related pathways. It was also noted that non-JAK signalling pathways were also
normalised, suggesting functional integration of JAK1 with parallel pathogenic signalling in RA effector
cells [522*].
Upadacitinib MOA assessed by genome-wide RNA expression
Lent and colleagues presented a poster on upadacitinib mechanism of action as assessed by
genome-wide RNA expression. Whole blood samples were analysed from a subset of patients from the
SELECT-NEXT study (upadacitinib 15 mg QD, n=99; placebo, n=100). Analysis of the top 100 most
affected transcripts by upadacitinib at Week 2, Week 4, and Week 12 identified modest but highly
significant modulation of a set of genes known to be differentially expressed in RA peripheral blood.
mRNA associated with B and T lymphocytes were increased, while mRNA associated with neutrophils
and monocytes were decreased, likely reflecting (at least in part) changes in leukocyte recirculation.
Pathway analysis demonstrated a broad inhibitory effect by upadacitinib on cytokines associated with
the pathobiology of RA, on intracellular signalling, and on toll-like receptor-pathways. Similarly, pathways
related to both innate and adaptive immune activation, leukocyte movement, phagocytic cell activity, and
leukocyte adhesion were predicted based on mRNA modulation, to be inhibited by upadacitinib.
Reciprocally, pathways associated with the numbers of B, T, and haematopoietic cells were predicted to
be activated by upadacitinib. In summary, upadacitinib normalizes key pathobiological pathways in RA
consistent with its clinical effect [545*].
*Chairman’s Pick