EULAR 2018 Review

Enhancing knowledge of the clinical importance of cytokine signalling
The Cytokine Signalling Forum
www.cytokinesignalling.com
EULAR 2018
Conference Highlights

EULAR 2018
Conference Highlights
Chairman’s Welcome
Dear CSF Member,
It is my pleasure to bring to you our review of the EULAR 2018 highlights, including a review of my ‘Chairman’s picks’.
This year, there continues to be considerable data published on JAK inhibition, with differences in the JAK-STAT
signalling pathway in synovial fibroblasts analysed in different joints [#OP0165], and the results of a systematic review
and meta-analysis of Phase 2 and 3 JAK inhibitor studies presented for the risk of patients developing malignancies or
serious infections [#OP0032].
It was exciting to see the Phase 3 data for upadacitinib: Burmester et al shared the results from patients with an
inadequate response to csDMARDs [#OP0036]; Genovese et al, presented the safety and efficacy of upadacitinib in
bDMARD inadequate responders [#SAT0219]; and Smolen et al evaluated updacitinib as monotherapy [#OP0035]. We
also saw the results of a Phase 2b/3 study of upadactinib in Japanese patients [#SAT0257].
Tofacitinib continues to be prominent this year: data from the ORAL Strategy trial were presented, including the impact of
glucocorticoids on tofacitinib efficacy and safety [#SAT0247], and the effect of live zoster vaccination [#SAT0220]; while
Kaine et al presented data on tofacitinib discontinuation and re-initiation in long-term extension studies [#OP0037].
Specific considerations included a comparison of the effectiveness of tofacitinib and bDMARDs in clinical practice
[#AB0485], improvements in left ventricular mass and cardiac output [#AB0489]; and identification of subgroups, which
could be used to develop personalised treatment algorithms [SAT0217].
Baricitinib showed interesting and varied data, with post hoc analyses from Phase 3 trials examining the impact of
controlling disease activity on physical function, and pain [#AB0258]. The effects of dose reduction were investigated
[#SAT0253] and hepatitis B reactivation was examined [#FRI0077]; efficacy and safety of baricitinib were reported from
the Phase 3 study RA-BALANCE, which enrolled patients in China, Argentina and Brazil [#SAT0218].
Beyond RA, there were data in psoriatic arthritis (PsA); the effects of tofacitinib on several composite endpoint measures
were presented from OPAL Broaden and Beyond [#THU0323]; and efficacy analysed by background methotrexate dose
[#AB0902], and by baseline demographics, disease activity and concomitant medications [#AB0921]. The efficacy and
safety of tofacitinib in patients with or without metabolic syndrome were also compared [SAT0317]. The safety,
tolerability and efficacy of tofacitinib over 36 months were presented from the ongoing OPAL Balance study [SAT0293].
Also of interest was an evaluation of the effect of tofacitinib on the ability of monocytes to differentiate into dendritic cells,
an important step in innate immunity [#AB0046].
The following pages provide a review of the highlights from EULAR 2018. Once again, thank you for your support, and
we hope you enjoyed your time at EULAR.
Yours,
Prof. Iain McInnes

Highlights from EULAR 2018
During the EULAR 2018 annual meeting, many presentations and posters reported on
cytokine signalling and related drugs. This document reviews the highlights.
Oral presentations
Abstract Session: RA therapy - new molecules and new strategies
Upadacitinib Phase 3 results
Phase 3 results for upadacitinib in 661 patients with RA and inadequate response (IR) to
csDMARDs were reported in an oral presentation by Burmester, et al. At Week 12,
significantly more patients receiving upadacitinib 15 mg and 30 mg QD versus placebo
achieved an ACR20 response (63.8% and 66.2% vs 35.7%, P

interruption visit, AEs, SAEs and discontinuations due to AEs occurred in 54.4%, 11.1%
and 1.5% of patients, respectively. The authors concluded that there was no loss of
efficacy after temporary withdrawal of tofacitinib, and that the safety profile was consistent
with that observed in previous LTE studies over 9 years [#0037].
Malignancy and serious infection rates in clinical trials of JAK inhibitors for RA
Lopez-Olivio, et al. presented a systematic review and meta-analysis of malignancies and
serious infections during randomised controlled trials of JAK inhibitors in patients with RA.
Thirty-one trials including 13 945 patients were included. Reported rates of malignancies
across studies ranged from 0% to 2.0%, and rates of serious infections ranged from 0.7%
to 5.4%. The most commonly reported malignancies were lung cancer, melanoma,
nonmelanoma skin cancer (NMSC), basal cell and squamous cell carcinoma. Patients
receiving the combination of JAK inhibitor plus MTX or JAK inhibitor monotherapy had
numerically higher rates of malignancies, compared with MTX between 12 and 24 weeks
before the rescue treatment was implemented (odds ratio [OR] 2.48, 95% confidence
intervals [CI] 0.76–8.11 and OR 1.39, 95% CI 0.21–9.11, respectively). JAK inhibitor
groups had similar rates of serious infections to those observed in the control groups.
However, higher rates of serious infections were observed in patients receiving higher
doses of JAK inhibitors [#0032].
Abstract Session: Fires and firefighters: switching the immune system on and off
Joint-specific differences in activation of the JAK-STAT pathway in RA
Masterson and colleagues presented findings on substantial quantitative and qualitative
differences in the JAK-STAT signalling pathway in synovial fluid (SF) from different joints.
Using synovial fluid isolated from knee, shoulder and hand joints from patients with RA and
osteoarthritis who were undergoing joint replacement surgery, the authors showed that the
JAK-STAT pathway was enriched in knee SF versus hand and shoulder SF. Knee SF
exhibited increased expression of JAK and STAT genes and enhanced signalling upon
stimulation with IL-6/sIL-6R. The authors suggest that RA in different joints might not be
equally sensitive to JAK-kinase inhibitors or blockade of IL-6, which has important
implications for clinical practice and drug discovery in this therapy area [#0165].

Poster Sessions
Poster Tour: Novel insights on non-biologics in RA
Efficacy and safety of baricitinib at 52 weeks in the Phase 3 RA-BALANCE trial
Li and colleagues presented 52-week efficacy and safety results from the Phase 3 RA-
BALANCE trial. The study enrolled patients from China, Argentina and Brazil with
moderately to severely active RA despite a stable background of MTX; patients received
baricitinib 4 mg QD or PBO for 24 weeks, when patients receiving placebo were switched
to receive baricitinib 4 mg QD until end of study. The primary endpoint, ACR20 at Week
12, was significantly greater with baricitinib compared with placebo (58.6% versus 28.3%,
P≤0.001). The ACR20 response observed at 12 weeks was maintained through 52 weeks
in patients receiving baricitinib (Week 24: 64.1%; Week 52, 62.8%). Significant
improvements in HAQ-DI physical function (PF), duration and severity of morning joint
stiffness, and worst tiredness were observed at Week 12 with baricitinib versus placebo.
Treatment-emergent adverse events (TEAEs) and serious infections during Weeks 0–24
were reported in 74.5% and 42.1% of baricitinib patients (respectively) compared with
62.1% and 28.3% of patients receiving placebo. No major adverse cardiovascular events
(MACE), deaths, TB, venous thromboembolisms or malignancies were reported through
Week 52 with baricitinib, and no unexpected safety signals were observed [#0218].
Upadacitinib Phase 3 study results
A poster by Genovese, et al. presented the results of a Phase 3, randomised, placebocontrolled
trial of upadacitinib in patients with active RA and an inadequate response or
intolerance to bDMARDs. In this study, patients received upadacitinib 15 mg or 30 mg QD,
or placebo, followed by upadacitinib 15 mg or 30 mg QD starting at Week 12. Compared
with placebo, more patients receiving upadacitinib achieved the primary endpoints of
ACR20 and proportion achieving DAS28CRP≤3.2 (both at Week 12). Among patients with
an inadequate response to multiple bDMARDs/MOAs, and those with lack of efficacy for
alpha-IL-6, the proportions achieving ACR20 on upadacitinib versus placebo were
comparable to the overall treated population. Overall rates of AEs were slightly higher for
upadacitinib 30 mg QD versus upadacitinib 15 mg QD, and there were more serious
infections and HZ cases in patients receiving upadacitinib 30 mg. PE was reported in two
patients through Week 12, and four more patients through Week 24; all had risk factors for
DVT/PE. One death in each upadacitinib dose group was reported. The overall safety
profile was considered consistent with Phase 2 and other Phase 3 studies of upadacitinib
[#0219].
Tofacitinib and the effect of live zoster vaccine on herpes zoster events in RA
Calabrese, et al. presented an evaluation of LZV in a subset of 1146 patients with RA
treated with tofacitinib with or without MTX, and adalimumab plus MTX in ORAL Strategy.
A total of 216 patients received vaccination with LZV. No patients had zoster-like lesions
within 42 days of vaccination; one had vaccination-site erythema. In the overall study
population, the incidence rate of HZ was similar between tofacitinib monotherapy and
adalimumab plus MTX, and numerically higher with tofacitinib plus MTX. Overall, 18
patients had HZ; only three vaccinated patients had HZ. No events were serious, and only

1 case was multidermatomal. Among the patients who were not vaccinated, 15 had HZ,
there were 2 serious HZ events, 2 multidermatomal events and 1 disseminated event
[#0220].
Identification of heterogeneous phenotypic subgroups of patients with RA
Bykerk and colleagues reported that it is possible to identify heterogeneous phenotypic
subgroups with distinct disease activity in patients with RA who are csDMARD-IR and
treated with tofacitinib. Models were based on pooled data from Phase 3 studies of
tofacitinib 5 mg BID. The groups were characterised by differences in disease activity and
patient-relevant outcomes, including baseline pain and physical function. The authors
proposed that the identification of distinct disease trajectories could be used to develop
personalised treatment algorithms incorporating clinical and molecular phenotypes
[#0217].
Poster Tour: Breakout news on non-TNF biologics in RA
Real world evidence: bDMARD treatment persistence and reasons for discontinuation
A poster on reasons for bDMARD cessation and subsequent persistence of second-line
treatment in a large real world rheumatoid arthritis registry was presented by Youssef, et
al. The analysis included patients aged ≥18 years with confirmed RA who were treated
with first line b/tsDMARDs (1 st August 2010 to 30 th June 2017) by physicians participating
in the OPAL-QUMI database. A total of 6914 patients received first line b/tsDMARDs.
Treatment was stopped in 38% of patients; 34% stopped within 6 months of initiation, with
the highest and lowest percentage observed in patients receiving tofacitinib (54%) and
tocilizumab (17%), respectively. The most common reasons for stopping therapy within 6
months were lack of efficacy (45%>abatacept, 44%>TNFis, 33%>tofacitinib and
27%>tocilizumab) and adverse reactions (21%> tofacitinib, 20%> tocilizumab,
15%>TNFis, 13%>abatacept). The percentage of patients remaining on 2nd line
b/tsDMARD treatment after stopping first line TNFis due to lack of efficacy was the highest
at 6 months with tocilizumab (78%) and at 12 months with rituximab (75%) [#0165].
Poster Tour: The hydra beast in RA: a multifaceted disease
Tofacitinib development programme: liver enzyme abnormalities
Soriano, et al. reported a prevalence of hepatic steatosis of 1.6% in 10,212 patients across
the tofacitinib RA, PsA and PsO programmes (1.3% in RA, 3.8% in PsA and 1.6% in PsO).
In both tofacitinib- and placebo-treated patients, the incidence of elevated total bilirubin,
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >1x ULN up to
Month 3 was higher in patients with hepatic steatosis than in those without, across
indications. The incidence of elevated total bilirubin, AST and ALT >3x ULN up to Month 3
was low across indications, irrespective of hepatic steatosis [#0099].

Poster sessions I, II and III
Upadacitinib efficacy and safety in RA
FitzGerald, et al presented findings from the Phase 3 SELECT-NEXT (n=661) and
SELECT-BEYOND (n=498) trials on the speed of response to upadacitinib across disease
measures. In these cohorts of patients with RA and an inadequate response to csDMARDs
or bDMARDs, those receiving upadacitinib at either 15 mg or 30 mg QD were more likely
to achieve clinical responses at significantly earlier timepoints compared with patients
receiving placebo. The median times to achieve ACR20 were 4 weeks with upadacitinib 15
mg QD, 2–3 weeks with upadacitinib 30 mg QD, and 12 weeks with placebo. The median
time to low disease activity (LDA) by CDAI and SDAI was approximately 12 weeks across
upadacitinib doses and populations; patients receiving placebo did not achieve this
measure within that time. The time taken to achieve various clinical responses was
consistent irrespective of having an inadequate response to csDMARD or bDMARD
[#0239].
Vollenhoven, et al. examined upadacitinib efficacy at 12 weeks of treatment (as per T2T
recommendations) in the SELECT-NEXT and SELECT-BEYOND trials. In both
populations of patients with RA, significantly more patients on upadacitinib versus placebo
achieved an ACR50 response. Among ACR50 responders at 12 weeks, approximately
one-half of csDMARD-IR patients and one-third of the bDMARD-IR patients achieved an
improvement in all 7 ACR components [#0244].
Genovese, et al. presented the long-term safety and efficacy profile for upadacitinib from
an ongoing open-label, long-term extension (OLE) of two Phase 2 studies (BALANCE-
EXTEND). This included 493 patients with RA, with a total of 725 patient-years of
cumulative exposure. The event rate per 100 patient years (E/100PY) was 170.5 for any
AE in the OLE, 9.4 for SAEs, 2.3 for serious infection, 3.7 for HZ, 0.8 for malignancies
excluding NMSC, and 0.7 for adjudicated cardiovascular events. There were 2 deaths (1
sudden death adjudicated as unknown cause, and 1 due to Hodgkin’s lymphoma). Efficacy
was maintained in patients receiving 6 mg upadacitinib BID from Day 1 of the OLE who
completed Week 72 (55% of patients met ACR70, and 80% were in LDA by DAS28-CRP
and CDAI) [#0236].
The results of a Phase 3/4, randomised, placebo-controlled, double-blind study of
upadacitinib in Japanese patients with active RA and an inadequate response to
csDMARDs were presented in a poster by Tanaka, et al. A total of 197 patients received
treatment and 187 completed the double-blind period. ACR20 rates at 12 weeks in patients
receiving upadacitinib 7.5, 15, and 30 mg or placebo were 75.5%, 83.7%, 80% and 42.9%,
respectively. ACR50 and ACR70 responses were achieved by significantly higher
proportions of patients receiving upadacitinib versus placebo; more patients receiving
upadacitinib 15 mg and 30 mg achieved these responses compared with those receiving
upadacitinib 7.5 mg. The overall safety and tolerability profile was consistent with that
observed in Phase 2 and 3 studies to date. Rates of any AEs, SAEs and infections were
numerically higher in patients receiving upadacitinib 30 mg compared with the lower
upadacitinib doses and placebo groups; CPK elevations and lymphopenia occurred more
frequently with upadacitinib 30 mg [#0257].

Effect of upadacitinib on patient-reported outcomes in RA
Strand, et al. presented two posters on patient-reported outcomes (PROs) with
upadacitinib in the SELECT-NEXT and SELECT BEYOND studies. A total of 661 patients
with active RA and an inadequate response to csDMARD were included in the analysis of
PROs in SELECT-NEXT. Treatment with upadacitinib 15 mg or 30 mg daily for 12 weeks
resulted in significant and clinically meaningful improvements in physical function, pain,
fatigue, morning stiffness, QoL and work instability. Numbers Needed to Treat (NNT) with
upadacitinib ranged from 4 to 8 patients [#0254]. A total of 498 patients with active RA and
an inadequate response to bDMARDs were included in the analysis of SELECT-BEYOND.
Compared with placebo at Week 12, upadacitinib-treated patients reported higher
responses that were statistically significant and clinically meaningful for HAQ-DI, PtGA
pain, pain, duration and severity of morning stiffness and SF-36 Physical Component
Summary (PCS). NNT with upadacitinib ranged from four to eight patients in this difficultto-treat
cohort [#0255].
Tofacitinib efficacy and safety in RA
Fleischmann and colleagues presented a post hoc analysis of the ORAL Strategy study
describing the impact of background glucocorticoids on the safety and efficacy of tofacitinib
(with and without MTX) and adalimumab with MTX. Patients with RA were randomised
1:1:1 to receive tofacitinib 5 mg BID, tofacitinib 5 mg BID plus MTX, or SC adalimumab 40
mg (every other week) plus MTX. In the cohort of 1146 patients who were randomised and
treated, efficacy endpoints (ACR50 response rate, LDA, remission rates, change in HAQ-
DI score) were generally similar for each treatment group when stratified by glucocorticoid
use. Unexpectedly, glucocorticoid use did not appear to be associated with higher rates of
AEs, discontinuations due to AEs, serious infection events, and SAEs [#0247].
Cumulative probability plots showing clinical and functional efficacy across treatments for
patients with RA in the ORAL Strategy study were presented by Takeuchi, et al. The
proportion of patients who achieved responses of ACR20, ACR50 and ACR70 was similar
for tofacitinib 5 mg BID plus MTX, and adalimumab SC 40 mg (every other week) plus
MTX every other week but was numerically smaller for tofacitinib 5 mg BID monotherapy.
Reductions from baseline in HAQ-DI were similar across treatment groups, although a
slightly higher proportion of patients who received tofacitinib monotherapy reported an
increase in HAQ-DI compared with other treatments. These data are consistent with the
primary ORAL Strategy findings [#0252].
Wiesenhutter examined the utility of various disease activity measures (DAMs) for clinical
decision making during implementation of a treat-to-target (T2T) strategy, following the
initiation of tofacitinib (n=39) and TNFis (n=40). Patients at a rheumatology clinic
underwent disease activity measure (DAM) assessments, which included conventional
clinical assessments, DAS28CRP, and the CDAI, as well as the ultrasound power Doppler
joint count (UPDJC) and multi-biomarker disease activity score (MBDA). Patients
underwent regular assessments, and if found to have inadequate control, changes were
made in their clinical regimen and reassessment was performed 3 to 6 months later. All of
the DAMs resulted in significant clinical responses with the exception that following the
initiation of tofacitinib, the MBDA did not result in clinically significant improvement. When
individual biomarkers from the MBDA were analysed, TNFi therapy led to significant
reduction in 6 of 12 biomarkers (IL-6, TNF-R1, TNF-R2, MMP-2, SSA and CRP), whereas

treatment with tofacitinib lead to significant reduction of 2 (VCAM and resisten) and
borderline reduction in 2 (IL-6 and TNF-R1), and a significant increase in one (leptin).
[#0089].
Effect of tofacitinib on patient-reported outcomes in RA
Patient-reported outcomes (PROs) in the ORAL Strategy study were reported by Strand
and colleagues. Patients with RA and an inadequate response to MTX were randomised
1:1:1 to receive tofacitinib 5 mg BID, tofacitinib 5 mg BID plus MTX, or adalimumab 40 mg
(SC, Q2W) plus MTX; PROs were assessed at 6 and 12 months, and included HAQ-DI,
patient global assessment (PtGA) visual analog scale) VAS, pain VAS, SF-36 Health
Survey, EuroQol (EQ)-5D VAS, Work Productivity and Activity Impairment (WPAI) and
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Baseline and
disease characteristics were similar among the 1146 treated patients. At 6 and 12 months,
improvements in PROs were similar with tofacitinib plus MTX and adalimumab plus MTX,
and were numerically greater than with tofacitinib monotherapy [#0256].
Tofacitinib efficacy and safety in PsA
Helliwell, et al. showed that tofacitinib improved composite measures of disease in 2
Phase 3 studies of patients with PsA. Patients with active PsA and either an inadequate
response to ≥1 csDMARD and who were TNFi-naïve (OPAL Broaden; N=422) or with an
inadequate response to ≥1 TNFi (OPAL Beyond; N=394) were assessed for Psoriatic
Arthritis Disease Activity Score (PASDAS), DAS28-3(CRP), disease activity score for
reactive arthritis (DAREA)/ Disease Activity index for Psoriatic Arthritis (DAPSA) and
CPDAI. In each study, both 5 mg BID and 10 mg BID doses of tofacitinib showed
improvements in composite endpoints versus placebo at 3 months; the largest effect size
and standardised response means were observed for PASDAS [#0323].
A post hoc analysis of the OPAL Broaden and OPAL Beyond studies was presented by
Ritchlin and colleagues; this analysis examined tofacitinib efficacy and safety in patients
with PsA and comorbid metabolic syndrome (MetS) and included 294 patients with active
PsA plus MetS, and 416 patients with active PsA and without MetS. Tofacitinib efficacy
was generally similar in patients with and without MetS, as determined by ACR20
response rate, change in HAQ-DI, Psoriasis Area and Severity Index (PASI)75 response
rate, change in and PtGA VAS. In patients with MetS, AEs and SAEs occurred in 55.6%
and 2.0% (respectively) of patients receiving tofacitinib 5 mg, and in 42.6% and 2.0% of
those receiving tofacitinib 10 mg; corresponding rates in patients without MetS were 42.4%
and 1.4% (5 mg) and 54.8% and 1.5% (10 mg). The authors concluded that tofacitinib
showed a generally similar efficacy and safety profile in patients with PsA with or without
MetS [#0317].
Burmester, et al. reported minimal changes in absolute lymphocyte counts and lymphocyte
subset counts in tofacitinib-treated patients with PsA, up to 6 months. An analysis of
pooled data the Phase 3 OPAL Broaden and OPAL Beyond studies of tofacitinib in 816
patients with PsA who had an inadequate response to ≥1 csDMARD or ≥1 TNFi found
minimal decreases in total T cells (CD3+), cytotoxic T cells (CD8+) NK cells (CD16+56+)
and a numerical increase in B cells (CD19+). Up to Month 12, serious infections were
reported in seven tofacitinib-treated patients and one adalimumab-treated patient. There

was no suggestion of an increased risk of serious infection in any absolute lymphocyte
count category [#0330].
The third interim analysis of OPAL Balance, an open-label LTE study of tofacitinib in
patients with PsA, was reported by Nash, et al. Of the 686 patients treated in the study,
468 remained in the study at data cut-off. To 36 months, 2186 AEs were reported in 79.6%
of patients. SAEs, discontinuations due to AEs and serious infections were reported in
13.8%, 8.6% and 1.7% of patients, respectively.
HZ was reported in 2.9% of patients, MACE in 0.7%, malignancies in 3.5% (including 12
pts with NMSC) and uveitis in 0.3%. No AEs of GI perforation or inflammatory bowel
disease were reported. There were 5 deaths, none of which were attributed to treatment as
assessed by the investigator. The authors concluded that over 36 months in the LTE, the
safety profile of tofacitinib in patients with active PsA was generally similar to that of the
Phase 3 studies. Efficacy was maintained across multiple disease domains to Month 30
[#0293].
Effect of tofacitinib on patient-reported outcomes in RA, PsA and AS
Ogdie, et al. showed that tofacitinib treatment (5 mg BID or 10 mg BID) was associated
with a rapid and sustained reduction of pain in patients with RA, PsA and AS. In patients
with RA or PsA who were csDMARD-IR or TNFi-IR, mean Patient's Assessment of Arthritis
Pain (PAAP)-VAS at baseline (5 mg BID, range 55.7–65.7 mm; 10 mg BID, 54.4–60.1 mm)
decreased as early as Week 2 and continued to decrease through Month 6 (30.9–34.4
mm; 28.2–36.7 mm); decreases were numerically greater versus placebo and the
magnitude of change was similar in RA and PsA populations. Improvements in SF-36v2
and EQ-5D were observed in all four RA and PsA csDMARD-IR and TNFi-IR populations;
there were improvements in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
in the csDMARD-IR PsA and TNFi-IR PsA populations. In the AS population,
improvements from baseline in SF-36v2 Q7, SF-36v2 bodily pain (BP) domain, EQ-5D
Pain/Discomfort (PD) domain and BASDAI Q2, were observed at Week 12 and were
numerically greater than with placebo [#0221].
No evidence for increased risk of DVT or PE with tofacitinib across disease states
Mease and colleagues reported an analysis of DVT and PE across randomised clinical
studies of tofacitinib in patients with RA, PsO, PsA and ulcerative colitis (UC). Up to Month
3 in the placebo-controlled cohort, DVT and PE occurred in two patients receiving placebo
(n=1 RA, n=1 UC); no tofacitinib-treated patients had DVT or PE events. In the dose
comparison cohort, 2 DVT events occurred in tofacitinib-treated patients with RA (5 mg
BID, n=1; 10 mg BID, n=1) and 1 DVT event in a patient with PsA (10 mg BID, n=1); 2
DVT events occurred with MTX and none with adalimumab. With tofacitinib, 5 PE events
occurred in the dose comparison cohort, all in patients with RA (5 mg BID, n=2; 10 mg
BID, n=3). The authors concluded that there is no evidence for an increased risk of these
events with tofacitinib versus other therapies [#0243].

Baricitinib dose step-down following sustained disease control
The effects of baricitinib dose step-down in patients with RA who achieved sustained
disease control with baricitinib 4 mg were presented by Takeuchi, et al. Patients who
participated in the baricitinib Phase 3 LTE study and received baricitinib 4 mg for ≥15
months, and achieved LDA or remission, were re-randomised to continue baricitinib 4 mg
(n=374) or step-down to baricitinib 2 mg (n=376); patients could rescue to 4 mg. Most
patients in both groups maintained LDA or remission over the 48 weeks; however, dose
reduction to 2 mg resulted in significant increases in disease activity at 12, 24 and 48
weeks, and a shorter time to relapse compared with the 4-mg group. Rates of SAEs and
AEs leading to discontinuation were similar between groups; however, dose reduction was
associated with a lower rate of serious infections. Most rescued patients were able to
regain LDA or remission [#0253].
Baricitinib: HBV reactivation and autoantibody profiling
Harigai and colleagues presented the findings of a post hoc analysis examining hepatitis B
virus (HBV) reactivation in patients with RA who participated in 4 Phase 3 trials of
baricitinib. In a total of 2890 patients who received 1 or more dose of baricitinib (6993
patient-years exposure), 269 patients had baseline serology suggestive of prior infection
and post-baseline HBV DNA tests were performed in 290 patients. Approximately 12% of
baricitinib-treated patients with prior HBV infection later tested positive for HBV DNA (3%
were above the lower limit of detection); no patients developed clinical evidence of
hepatitis, and antiviral therapy was not commonly required [#0077].
An exploratory analysis of autoantibody profiles for response to baricitinib in patients with
RA and no or limited exposure to MTX was presented by Martinez-Gamboa, et al. Baseline
sera samples from patients participating in the Phase 3 trial RA-BEGIN were investigated
for auto-antibody class reactivity towards vimentin (V), modified by citrullation (MCV),
carbamylation (Carb) or acetylation. Seropositive patients with high titres of anti-MCV and
anti-CarbV at baseline showed better responses to baricitinib monotherapy or baricitinib
plus MTX for composite scores, and better response to baricitinib monotherapy in
structural progression outcomes [#0109]
Patient-reported outcomes with baricitinib
Bingham and colleagues reported an analysis of PROs from the Phase 3 RA-BEAM and
RA-BEACON trials of baricitinib in patients with RA with an inadequate response to MTX.
FACIT-F and SF-36 BP scores were converted to Patient-Reported Outcomes
Measurement Information System (PROMIS) Fatigue and Pain Interference (PI) scores, to
permit comparisons with the general population. In both studies, baricitinib was associated
with clinically relevant improvements through 24 weeks versus placebo for PROMIS
fatigue and PI scores [#0106]. In a separate analysis, the authors converted HAQ-DI
scores to PROMIS Physical Function (PF) scores. Treatment with baricitinib was
associated with clinically relevant improvements in PROMIS PF versus placebo through 24
weeks in both studies, and versus adalimumab through 52 weeks in RA-BEAM [#0013].

Real-world evidence: patterns of use with JAK inhibitors
Chastek, et al. reported real-world patterns of use in biologic-naïve and biologicexperienced
patients with RA who were newly prescribed a JAKi. In this retrospective
analysis of 1059 patients (80.2% biologic-experienced), 72.4% of patients were not
persistent for the 1-year following initiation of a JAKi, and 39.1% were not persistent
beyond 90 days. For non-persistent patients, 42% interrupted JAKi treatment and
restarted, 30% switched to a bDMARD and 28% discontinued. More biologic-naïve than
biologic-experienced patients neither initiated a bDMARD nor restarted a JAKi after
interruption (44.2% versus 23.3%, respectively; P

Publication only
Efficacy and safety of tofacitinib for RA in clinical practice
Aramaki, et al reported 52-week efficacy and safety with tofacitinib in patients with RA
treated in routine clinical practice in Japan. In this cohort of 77 patients (n=23 biologicalnaïve)
who all received tofacitinib 5 mg BID, the drug survival rate was 73.8% at 52 weeks;
n=27 patients were treated for 104 weeks. Mean ESR-DAS decreased from 5.15 at
baseline to 3.52 at 24 weeks, and 3.59 at 52 weeks. Mean CDAI decreased from 21.5 at
baseline to 7.94 at 24 weeks, and 7.93 at 52 weeks. At 52 weeks, 16 patients (20.8%)
achieved remission (DAS-ESR

for discontinuing tofacitinib were insufficient response (n=23), GI symptoms (n=18),
infection (n=5), myalgia (n=2), remission (n=2), headache (2), cough, blue toe syndrome,
intolerance, heart burn, psoriasis, and increased liver enzymes (all n=1). The authors
concluded that tofacitinib is a safe and effective treatment option for patients with RA
[#0497].
Zengin and colleagues reported data from the Turkish TURKBIO registry on tofacitinib
efficacy and safety in 180 patients with RA. Median duration of disease activity was 14
years, and 75 patients had previously used ≥1 biologic agent. All disease activity
parameters were significantly reduced versus baseline after 12 weeks of treatment, with
6%, 59% and 27% of patients achieving remission, or with a moderate or high activity
level, respectively. Most disease activity parameters were maintained until Week 60, the
last examined time point. During the follow-up period, 9 AEs were observed [#0482].
Drug survival rates with tofacitinib in RA: a single-centre cohort study
Drug survival rates of tofacitinib in a single-centre cohort of 192 patients with RA with a
median disease duration of 10 years were reported by Karakoc, et al. Approximately half of
the cohort (48%) were biologic-naïve; tofacitinib was prescribed as monotherapy in 58% of
patients and in combination with csDMARDs in 42% of patients. Drug survival rates were
77% at 3 months, 69% at 6 months, 62% at 12 months, 54% at 18 months, 49% at 24
months and 49% at 30 months. Discontinuation of tofacitinib treatment occurred in 27% of
patients due to lack of response, and in 11% of patients due to side effects [#0502].
Tofacitinib dose escalation and subsequent reduction in patients with RA
Gaylis and colleagues reported data from a study of nine patients who were initially
unresponsive to treatment with tofacitinib 5 mg BID and who were subsequently dose
escalated to 10 mg BID to achieve LDA or remission. After 6 months of treatment with 10
mg BID and a sustained LDA or remission, the patients were reduced back to 5 mg BID;
six of nine patients were able to maintain LDA or remission over the following 6 months,
and three patients were dose escalated back to 10 mg BID and achieved treatment target.
These findings confirm that 10 mg BID of tofacitinib may be the effective dose required to
reach treatment target for some patients with active RA and suggest that there is
opportunity to reduce the escalated dose back down to the standard dose following
achievement of a target response [#0282].
Improvement of left ventricular mass and cardiac output with tofacitinib
In a cohort study, Kume, et al. showed that tofacitinib monotherapy improved left
ventricular mass and cardiac output in 24 patients with active RA (despite treatment with
csDMARDs) and chronic heart failure. Tofacitinib significantly attenuated left ventricular
mass as measured with cardio-MRI at baseline and 24 weeks; these effects were
independent of tofacitinib’s effects on disease activity. The authors propose that the JAK-
STAT pathway may be important for left ventricular hypertrophy, and that blockade of this
pathway by tofacitinib may prevent cardiovascular morbidity and mortality in patients with
RA and chronic heart failure [#0489].

A case study of vasculitis in a patient with RA treated with tofacitinib
Muraviev, et al. presented a case of polyarteritis nodosa (vasculitis) in a female patient
with RA. The patient was hospitalised in December 2016 due to painful eruption of
indurated nodules on her legs, ulceration of nodules on her legs, painful hip and ankle
joints and morning stiffness; the patient had been receiving tofacitinib 10 mg/day since
November 2015, with rapid achievement of minimum RA activity. Tofacitinib was
discontinued in June 2016 due to increasing lab activity of vasculitis. Histopathology
showed the presence of cutaneous and subcutaneous fat and destructive vasculitis, and
acute, predominantly lobular panniculitis, suggestive of polyarteritis nodosa and other
systemic vasculitis. A causal relationship between this adverse drug reaction and
tofacitinib therapy was assessed as probable (Naranjo scale) [#0413].
Musculoskeletal ultrasound for monitoring the effects of biologic therapy in RA
Yu and colleagues reported that musculoskeletal ultrasound (MSUS) was a useful tool for
monitoring and following-up the effects of biologic therapy in patients with RA, for the
assessment of inflammatory and destructive changes. In a real-world study of 18 patients
with RA who were treated with tofacitinib 5 mg BID for 12 weeks, there was a significant
correlation between MSUS scores and conventional (clinical and laboratory) measures of
disease activity [#0210].
Tofacitinib in patients with PsA: pooled sub-analyses of OPAL Broaden and OPAL Beyond
Kivitz, et al. investigated pooled data from OPAL Broaden and OPAL Beyond, looking at
the efficacy of tofacitinib by background MTX dose in patients with PsA. In total, data from
556 patients who received tofacitinib plus MTX or placebo plus MTX were included in this
analysis. Most patients were treated with background MTX at doses ≤15 mg/week (66.7%;
mean dose 12.6 mg/week) compared with >15 mg/week (33.3%; mean dose 19.8
mg/week). At Month 3, tofacitinib 5 and 10 mg BID were generally associated with
numerically greater ACR and HAQ-DI response rates and greater changes from baseline
in HAQ-DI score compared with placebo. The magnitude of tofacitinib effects on efficacy
outcomes appeared broadly similar between background MTX dose groups [#0902].
In a second pooled sub-analysis of the OPAL Broaden and OPAL Beyond studies,
Behrens and colleagues examined the impact of baseline demographics, disease activity
and concomitant medication on ACR20 response rate and HAQ-DI. Compared with
placebo, tofacitinib 5 and 10 mg BID consistently improved efficacy at Month 3 across all
predefined subgroups evaluated (race, ethnicity, gender, geographic region, PsA duration,
age, BMI, PsA subtype, distal inter-phalangeal joint involvement, arthritis mutilans status,
spondylitis status, baseline CRP, PASDAS, PASI score, DSS=0, concomitant csDMARD,
corticosteroid use), with the exception of current smoking status [#0921].
A novel mechanism of action for tofacitinib
Marzaioli, et al. reported preclinical results suggesting a novel mechanism of action for
tofacitinib. Pre-treatment of monocyte-derived dendritic cells (Mo-DC) from patients with
RA and PsA inhibited Mo-DC differentiation. Furthermore, the decreased ability of

monocytes to differentiate into dendritic cells translated into a functional impairment of
phagocytic ability. NOX5 protein expression was significantly decreased in pre-treated Mo-
DC from PsA patients, and to a lesser extent in cells from RA patients. The authors
proposed that inhibition of Mo-DC development by tofacitinib may alter migration of DC to
the joint and subsequent activation of the immune response [#0046].
Post hoc analyses of baricitinib Phase 3 studies
Hepatic safety in patients with RA who received isoniazid (INH) for latent TB (LTBI) was
reported by Hsieh et al. In this post hoc analysis of data from 3 Phase 3 baricitinib studies
(n=2516 patients; RA-BEAM, RA BUILD, RA BEACON), 246 patients reported LTBI and
169 had confirmed laboratory data and received INH as LTBI treatment. The percentage of
patients with greater than one times the ULN levels of ALT was numerically higher in
patients in the INH group versus no INH, and was consistent across placebo, baricitinib
and adalimumab treatment groups. No treatment interruptions or discontinuations were
reported in INH users in the baricitinib or adalimumab groups. The authors concluded that
the data do not suggest an increased hepatic safety risk in patients receiving baricitinib
and INH concomitantly [#0098].
A post hoc analysis of the RA-BEAM and RA-BEGIN studies in patients with RA was
reported by de Vlam, et al. The analysis showed that controlling disease activity by
achieving LDA or remission increases the chance to regain normal physical function and
relieve pain, independent of treatment (baricitinib monotherapy, baricitinib plus MTX or
adalimumab). The data from RA-BEAM may indicate that achieving no/limited pain at
Week 12 may be more likely with baricitinib compared with adalimumab, when achieving
remission (83% versus 73%) [#0258].
Pope and colleagues reported a post hoc analysis of RA-BEAM. The authors showed that
reductions in pain and fatigue were associated with improvements in regular daily
activities, presenteeism and work productivity, with patients who reported lower levels of
fatigue and pain tending to experience greater improvements compared with patients with
higher levels of pain and fatigue. When patients achieved a minimal level of pain (pain
VAS ≤10 mm), similar improvements in presenteeism and work productivity were observed
regardless of fatigue level. Similar results were observed between treatment groups
[#0240].
Phase 1 pharmacokinetic studies with upadacitinib in volunteers with renal impairment
Mohamed, et al. reported results from a Phase 1 study that examined the
pharmacokinetics of upadacitinib in 24 volunteers with either normal renal function or mild,
moderate or severe renal impairment. In participants with mild, moderate and severe
hepatic impairment, point estimates for plasma exposure ratios following a single 15 mg
dose were 1.18, 1.33 and 1.44 for AUC and 1.06, 1.11 and 1.14 for maximum plasma
concentration, relative to participants with normal renal function. The authors concluded
that renal impairment has only limited effect upon upadacitinib pharmacokinetics, with
mean plasma exposure in participants with severe renal impairment within 44% of that
observed in patients with normal renal impairment [#0479].

In a separate dedicated Phase 1 study, Mohamed and colleagues examined the
pharmacokinetics of upadacitinib in 18 volunteers with either normal renal function, or mild
or moderate renal impairment. In participants with mild and moderate hepatic impairment,
upadacitinib exposure ratio central values following a single 15 mg dose were 1.28, 1.24
for AUC and 1.04, and 1.43 for maximum plasma concentration, relative to participants
with normal renal function. The authors concluded that renal impairment has very limited
effect upon upadacitinib pharmacokinetics (

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Enhancing knowledge of the clinical importance of cytokine signalling
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EULAR 2018
Conference Highlights