ACR 2018 Congress Review

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

ACR 2018
Conference Highlights
Chairman’s Welcome
Dear CSF Member,
It is my pleasure to welcome you to our review of the ACR 2018 highlights, which includes my ‘Chairman’s Picks’: abstracts
presented at ACR that I feel have the most significant impact on cytokine signalling science.
This year it was exciting to see more data supporting the use of JAK inhibitors in rheumatoid arthritis, with new Phase 3 data
released for two JAK inhibitors in late stage development. Two Phase 3 peficitinib abstracts are presented with results from
two different patient populations; DMARD inadequate responders [#887] and methotrexate inadequate responders [#888].
In addition, upadacitinib Phase 3 data continues to be presented following the abstracts at EULAR earlier this year. Smolen
presents data on upadacitinib monotherapy in methotrexate inadequate responders [#889], followed by van Vollenhoven
investigation of upadacitinib monotherapy in methotrexate-naïve patients [#891]. The upadacitinib Phase 3 data also includes
an upadacitinib comparison study in methotrexate inadequate responders, presented by Fleischmann [#890].
Updates on the long-term safety profile of baricitinib are presented in a 6-year integrated safety analysis presented by
Genovese [#962], with a focus on cardiovascular safety discussed by Weinblatt [#2815].
Similar data is presented on tofacitinib with in a longer-term safety analysis study containing data up to 9.5 years [#963].
Cardiovascular disease risk associated with tofacitinib was evaluated in comparison to csDMARD in patients with RA
[#2817], and herpes zoster risk is analysed in an abstract by Curtis, using data over a 5-year period [#885]. Tofacitinib clinical
effectiveness is also evaluated, in an observational cohort by Cohen [#580].
We also have long-term safety data on filgotinib in patients with RA, using data up to 132 weeks [#2551]. Outside RA,
filgotinib is showing positive Phase 2 data in psoriatic arthritis and in csDMARD inadequate responders presented by Mease
[#1821].
Here, we provide a review of the highlights from ACR 2018, including my ‘Chairman’s Picks’. As always, thank you for your
continued support of the Cytokine Signalling Forum and we hope you enjoyed your time at ACR this year!
Yours,
Prof. Iain McInnes

Highlights from ACR 2018
During the ACR 2018 annual meeting, many presentations and posters reported on cytokine signalling
and related drugs. This document reviews the highlights.
Oral presentations – ACR Concurrent Abstract Sessions
Plenary Session II
Filgotinib in cDMARD-IR PsA: Phase 2 study results
Mease and colleagues presented the findings of a 16-week Phase 2 randomised, placebo-controlled trial
evaluating filgotinib in patients with PsA and an inadequate response to cDMARDs. For filgotinib and
placebo patients respectively, ACR20 response at Week 16 (primary endpoint) was achieved by 80.0%
and 33.3% (p

The results of a third Phase 3 study of upadacitinib versus MTX in MTX-naïve patients with moderate-tosevere
RA (SELECT-EARLY) were reported by van Vollenhoven and colleagues. A total of 947 patients
were randomized 1:1:1 to once-daily upadacitinib at 15 mg or 30 mg, or weekly MTX (titrated by Week
8). Both primary endpoints (ACR50 at Week 12 [FDA], or the proportion of patients achieving DAS28-
CRP

RA –Treatments II: Safety
Long-term safety with baricitinib and tofacitinib
Genovese et al. presented the long-term safety and efficacy profile for baricitinib up to 6 years from an
ongoing open-label, long-term extension (OLE) study. This included 3492 patients with RA, with a total
of 7860 patient-years of exposure. AE IR did not increase with increased exposure compared with a
previous analysis in in 2016. Malignancy (excluding non-melanoma skin cancer) IRs were 0.5 and 1.2
for 2 mg and 4 mg, respectively (as-treated analysis) and 0.8 and 0.8 (as-randomized analysis). In the
all-baricitinib-RA group, IRs for gastro-intestinal perforation and tuberculosis were 0.04 and 0.14,
respectively [#962].
Data on the long-term safety of tofacitinib up to 9.5 years were presented by Cohen and colleagues,
representing the largest integrated safety analysis of tofacitinib to date (7061 patients representing
22,875 patient years of tofacitinib exposure). The most common treatment-emergent AEs (MedDRA
v20.0 preferred term) were viral upper respiratory tract infection (17.3%), upper respiratory tract infection
(17.2%), and urinary tract infection (11.8%). The following IRs were reported: SAEs (9.0), serious
infections (2.5), herpes zoster (3.6), opportunistic infections (0.4), TB (0.2), malignancies (0.8), nonmelanoma
skin cancer (0.6), lymphomas (0.1), GI perforations (0.1), MACE (0.4),
DVT (0.12) and pulmonary embolism (0.12). There were 59 deaths (IR 0.3) [#963].
RA – Diagnosis, Manifestations, & Outcomes I: Other Co-Morbidities
Tofacitinib safety: herpes zoster risk by concomitant MTX or GC use
Herpes Zoster (HZ) risk in tofacitinib users with and without MTX and glucocorticoid (GC) use was
evaluated by Curtis et al. MarketScan and Medicare data (2011-2016) was used to identify all
rheumatologist-diagnosed RA patients initiating tofacitinib. In 8030 new tofacitinib users, the crude HZ
incidence with tofacitinib use was numerically lower in the absence of GC (e.g. 3.4/100py with MTX and
3.7/100py without MTX) and an approximately two-fold increased crude incidence of HZ was observed
for tofacitinib users receiving either GCs alone (6.0/100py) or both MTX and GCs (6.5/100py). After
multivariable adjustment, the hazard ratio for HZ associated with tofacitinib was unchanged when given
with MTX but approximately double when tofacitinib was given with GC. These analyses suggest that HZ
risk in tofacitinib users is doubled with GC exposure and that concomitant MTX did not confer increased
risk [#885].
RA – Diagnosis, Manifestations, & Outcomes IV: CV Co-morbidities
Long-term CV safety with baricitinib in RA
An analysis of CV safety in patients treated with baricitinib for up to 6 years was presented by Weinblatt
and colleagues. Data were pooled from 8 Phase 1–3 studies and analysed in three sets: all patients
exposed to any baricitinib dose; studies comparing baricitinib 4-mg QD with placebo up to 24 weeks;
and studies with baricitinib 2 mg and 4 mg QD, including long-term extension data. A total of 3492
patients were exposed to baricitinib (7860 PY), 78.0% for ≥1 year and 51.2% for ≥2.5 years. For arterial
thrombotic events (ATE) and MACE, the frequency of reported events and IRs were low, comparable
across treatments and analysis sets, and did not increase with prolonged exposure. For DVT/PE, 6
events were reported for baricitinib 4 mg and none with placebo during the 24-week placebo-controlled
period. After longer exposure, DVT/PE IRs were comparable between baricitinib 2 mg and 4 mg doses.
In all patients exposed to any baricitinib dose, IRs were stable over time (overall IR 0.53) [#2815].

Incident CVD rates in RA: bDMARDs and tofacitinib versus csDMARDs
Ozen et al reported the comparative effects of bDMARDs and tofacitinib against csDMARDs on incident
CVD. RA patients with ≥1 year participation in FORWARD (1998 through 2017), The National Databank
for Rheumatic Diseases, were assessed for incident CVD. A total of 1561 CV events were identified in
17363 RA patients with a median of 4.1 years of follow-up. The IR of CVD for the entire cohort was 1.78
per 1000 patient-years. In an adjusted model, a significant CVD risk reduction was seen with TNFi (HR
0.79, 95% CI 0.69-0.92) and abatacept (HR 0.53,
95% CI 0.30-0.92) compared to csDMARDs. In analysis of individual TNFi, although all TNFi
tended to be associated with decreased CV risk, only the risk with infliximab (HR 0.81 [0.67-0.98]) and
etanercept (HR 0.78 [0.64-0.95]) reached statistical significance [#2817].
RA – Etiology & Pathogenesis I
IL-6 and JAK-STAT signalling in RA
Hammaker and colleagues assessed how hip and knee fibroblast-like synoviocytes (FLS) in RA differ in
terms of the response to IL-6, to define the functional sequelae of joint-specific epigenetic imprinting.
RNA-seq data from RA FLS lines sourced from hip and knee arthroplasties were normalized and
principal component analysis was performed. The hip and knee FLS segregated after IL-6 treatment,
indicating that joint-specific differences are maintained after IL-6 treatment. Differentially expressed
genes were identified, focusing on hip vs knee differences. Knee FLS had significantly higher P-STAT3
than hip FLS at 30 minutes (p

SLE – Etiology & Pathogenesis I
Baricitinib-associated changes in type 1 interferon gene signature
Dörner and colleagues reported a dose-dependent decrease in the IFN signature in baricitinib-treated
patients with SLE in a Phase 2 trial. A total of 314 patients were randomised to receive baricitinib 2 mg
or 4 mg once daily for 24 weeks. At baseline, 70% of patients had an elevated IFN signature. Both
doses of baricitinib significantly reduced the IFN signature by Week 24 compared with placebo (p≤0.05),
with decreases observed as early as Week 2. In the patients who had a high IFN signature at baseline,
baricitinib 4 mg significantly reduced the IFN signature at Week 12 and Week 24 compared with placebo
(p≤0.01). The effect of baricitinib on IFN signature reduction did not correlate with the observed SLEDAI-
2K-defined clinical improvement at Week 24 [#1894].
SLE – Clinical I: Clinical Trials
Baricitinib in SLE – Phase II
Phase 2 study results for baricitinib in patients with SLE were reported by Wallace and colleagues. In
this placebo-controlled trial, patients with SLE who were receiving stable background therapy were
randomised to receive placebo or baricitinib (2 mg or 4 mg) once daily. At Week 24, a significantly
greater proportion of patients in the baricitinib 4 mg group compared to placebo achieved the primary
endpoint of resolution of SLEDAI-2K arthritis or rash (67% vs 53%,p

Poster Sessions – ACR Poster Session A
Rheumatoid Arthritis – Treatments: Strategy and Epidemiology
Baricitinib efficacy in RA
Taylor et al performed an analysis of data from RA-BEAM to assess if patients who received baricitinib
early attained added clinical improvement compared with patients with a delayed start of therapy.
Patients initially randomized to baricitinib 4 mg were considered the early start group and placebo
patients switched at Week 24 or rescued at Week 16 or later were considered to have a delayed start.
The early start group had significantly greater change from baseline up to Week 32 in CDAI and showed
greater and more rapid reduction in CDAI through the first 4 weeks (>50% reduction) compared with the
delayed start group. Similar results were seen for SDAI, DAS28-ESR and DAS28-hsCRP. The authors
concluded that while overall disease activity improvement was similar between groups, early start of
treatment with baricitinib provided faster efficacy [#546].
Fleischmann and colleagues evaluated the percentage of patients originally randomized to baricitinib 2
mg or 4 mg in the Phase 3 RA-BUILD study, and rescued in the study and/or in the long-term extension
study; the clinical benefits post-rescue were also assessed. Fewer patients originally assigned to
baricitinib 4 mg in RA-BUILD required rescue compared to patients assigned to 2 mg (36% versus 52%,
respectively). Disease activity assessed by CDAI and patient-reported pain improved following rescue
from baricitinib 2 to 4 mg: clinically meaningful response rates in CDAI (≤10) and pain improvement
increased and stabilized over time in the baricitinib-treated population. Patients rescued in RA-BEYOND,
after being treated with baricitinib in RA-BUILD, had less disease activity compared to patients rescued
in RA-BUILD, at the time of rescue [#574].
Fautrel et al assessed pain and HAQ-DI for baricitinib monotherapy from a randomized, MTX-controlled
trial (RA-BEGIN) vs adalimumab, tocilizumab, and tofacitinib monotherapy from similar randomized,
MTX-controlled trials in csDMARD/bDMARD naïve RA patients (PREMIER, AMBITION and FUNCTION,
and ORAL-START, respectively). A matching-adjusted indirect comparison approach was used. At
Week 24, baricitinib showed numerically greater improvement over MTX in pain than that for the
bDMARD monotherapies; statistically significant pain improvements were observed for baricitinib vs
adalimumab and tocilizumab. Baricitinib-treated patients showed significantly greater improvement in
HAQ-DI at Week 24 than tocilizumab and adalimumab but not tofacitinib. The results suggest a greater
pain reduction and improved physical function for baricitinib monotherapy vs tocilizumab and
adalimumab monotherapy [#599].
Tofacitinib efficacy and safety in RA
Razmjou and colleagues report the findings of a pilot study that evaluated whether baseline
musculoskeletal ultrasound (MSUS) and multi-biomarker disease activity (MBDA) scores or early
changes can predict 12-week clinical response in patients with RA who are treated with tofacitinib. A
total of 25 patients with RA were treated with open-label tofacitinib 5 mg BID. There was significant
improvement in power Doppler US (PDUS), grey scale ultrasonography (GSUS), MBDA score, DAS28,
and CDAI over 12 weeks (all p

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. Responses of approximately ≥ACR80 were achieved by a similar
proportion of patients in each treatment group. 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 [#607].
Tofacitinib persistence, adherence and effectiveness were examined by Cohen and colleagues in a
retrospective cohort study of patients with RA by 12-month post-index MTX status (persistent: ≤60-day
gap; discontinued: >60-day gap; interrupted: >60-day gap with ≥1 subsequent MTX claim 12 months
post-index). This analysis of US-based claims data (n=479 patients) showed that patients who initiate
tofacitinib with oral MTX can discontinue MTX with similar persistence, adherence and effectiveness,
and lower RA-related total/pharmacy costs 12-months post-index vs MTX-persistent patients. The
authors caution that these findings are limited by the use of claims data, suggesting that further analysis
with a larger sample size is required [#581].
Remission and radiographic non-progression in patients with early rapid radiographic progression RA
assessed in a single-blind, randomised controlled trial were reported by Kume et al. A total of 39 patients
were randomised to receive either tofacitinib alone or tofacitinib plus intra-articular steroid injection
(IASI); all patients received MTX 10–22 mg/wk). Clinical remission (SDAI

Real-world data for patients with RA from the St. Gallen and Aarau cohort who were treated with
tofacitinib were reported by Mueller et al. A total of 144 patients were included in the analysis, 83.9% of
whom had been exposed to ≥1 biological agent. Tofacitinib was initiated at a dose of 5 mg BID. LDA or
remission was achieved by 58.2% and 49.5% of patients (median 319 and 645 days), respectively;
these rates were significantly higher in patients naïve to biologic agents compared with those preexposed
to biologics. Reasons 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 finger
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 and that the rate of
patients achieving LDA or remission is significantly higher in patients naïve to biologics [#586].
The results of an observational study of tofacitinib versus TNFis (etanercept, adalimumab or golimumab)
were presented by Hsieh and colleagues; data were sourced from a Taiwanese registry (XTRA; N=211
patients). TNFi initiators had higher baseline median DAS28-ESR and CDAI scores (6.16 and 36.6,
respectively) vs tofacitinib initiators (5.74 and 28.7, respectively) (p

Rheumatoid Arthritis – Animal Models
Discovery of DWP213388, a potent ITK and BTK dual target inhibitor
Jung and colleagues reported the development of a novel interleukin-2-inducible T-cell kinase (ITK) and
Bruton’s tyrosine kinase (BTK) dual target inhibitor, DWP213388. In preclinical in vitro models,
DWP213388 was a potent inhibitor of ITK and BTK (IC values of 1.4 nM and 0.7 nM, respectively) and
was highly selective against ITK and BTK, yet demonstrated low affinity toward EGFR. In a mouse CIA
model, treatment of DWP213388 improved arthritis in a dose-dependent manner and histological
damages in ankle and knee were markedly improved. The authors concluded that DWP213388 may
serve as a next generation therapeutic agent for autoimmune diseases, including RA [#37].
Spondyloarthritis Including Psoriatic Arthritis – Clinical: Imaging, Clinical Studies, and Treatment
Tofacitinib in PsA and RA
A post-hoc analysis examining the effect of tofacitinib 5 mg BID on laboratory values in patients with PsA
or RA was presented by Rigby and colleagues. For analysis of patients with active PsA treated with
tofacitinib (N=348), data were pooled from 2 Phase 3 studies and an ongoing long-term extension study.
For analysis of patients with moderate or severe RA treated with tofacitinib (N=3040), data were pooled
from 8 Phase 2 studies, 7 Phase 3 studies and 1 LTE study. Change from baseline in hematologic
(haemoglobin, neutrophils, lymphocytes) and lipid (LDL-cholesterol, HDL-cholesterol, total cholesterol,
triglyceride) levels and key liver tests (bilirubin, ALT, AST) creatine kinase, creatinine, and C-reactive
protein levels were assessed. Following initial increases/reductions, key laboratory values remained
stable to Month 12 in both PsA and RA, except for a reduction in lymphocyte levels, which stabilized at
later time points (data not shown). In both PsA and RA, ≤3.0% of patients met discontinuation criteria for
any laboratory values [#685].

ACR Poster Session B
Rheumatoid Arthritis – Diagnosis, Manifestations, and Outcomes: Diagnosis and Prognosis
Baseline characteristics predict low disease activity with tofacitinib
A post-hoc analysis of the ORAL-Strategy study examined baseline characteristics in MTX-IR patients with
RA who received tofacitinib 5 mg BID monotherapy. Kaine and colleagues reported that baseline covariates
significantly associated with any of the three LDA measures at Month 6 included age, disease severity (e.g.
TJC, DAS28-4[ESR], SDAI and RF/anti-citrullinated protein antibody status) and SF-36 PCS. Multivariable
analyses will be performed to further explore these associations [#1495].
Rheumatoid Arthritis – Treatments: PROs, Safety and Comorbidity
Tofacitinib real-world data
The impact of obesity on the achievement of LDA in RA patients treated with a JAKi was reported in a
poster by Meißner and colleagues. Data were sourced from the German prospective longitudinal
observational cohort RABBIT (Rheumatoid Arthritis: Observation of biologic therapy). In 539 patients
who started treatment with a JAKi (baricitinib, n=355; tofacitinib, n=184), despite lower frequency of
seropositivity, obese patients presented with higher values for DAS28 and fatigue, and had a worse
physical function at baseline. LDA was reached within the first 6 months of treatment by 42% of patients
with normal weight (BMI

Tofacitinib safety and tolerability
In a cohort study, Kume et al showed that tofacitinib monotherapy improved left ventricular mass and
cardiac output in 42 patients with active RA (despite treatment with csDMARDs) and chronic heart
failure. Tofacitinib significantly attenuated left ventricular mass (as measured with cardio-MRI) and
cardiac output, 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 [#1527].
A poster by Curtis and colleagues reported pooled data from two LTE studies (ORAL Sequel and
NCT00661661) in patients with RA. The authors examined patient characteristics associated with
discontinuation of tofacitinib over a 9.5-year period. Patients who discontinued had a longer disease
duration at baseline, and were more likely to use glucocorticoids, be smokers/ex-smokers, and be from
USA/Canada, than completers. Patients who discontinued ≤1year had higher disease activity than those
who discontinued >1 year; and patients who discontinued >1 year had higher disease activity than
completers, supporting close monitoring of patients. Of patients with TEAEs, discontinuation due to
TEAEs was more frequently observed in patients who discontinued during the first year [#1519].
An analysis from the Rhumadata ® clinical database and registry evaluating data from patients exposed
to tofacitinib since the drugs approval in Canada was presented by Choquette and colleagues. In the
131 patients exposed to tofacitinib since its launch, the majority were female (82%) with a mean age and
disease duration at treatment initiation of 58.1 and 11.5 years, respectively. At the time of the analysis,
63% remained on treatment; reasons for stopping were inefficacy (66%), adverse events (21%),
infections (4%) and other/unknown (11%). The 6-, 12-, 24-, and 36-months’ retention rates of patients
treated with tofacitinib were 75.0, 65.4, 54.7, and 52.3%, respectively, and patients treated with and
without MTX had similar retention curves. Patients stopping and remaining on therapy showed
improvements (decreases) of 3.3 and 10.7 units in CDAI, respectively. At their last evaluation, 14.8%, of
patients were in remission, and 3.3%, 55.7% and 26.3% had low, moderate and high disease activity. In
summary, patients showed improvement in their disease activity score compared to baseline and the
addition of MTX did not provide better sustainability over time [#1531].
Tamura and colleagues provided an interim report of tofacitinib safety based on all-case post-marketing
surveillance (PMS) data following approval in Japan. Overall, 3929 tofacitinib-treated patients with
1704.1 patient-years of exposure were included in the 6-month interim analysis. Of these, 22.7%
discontinued treatment, mainly due to AEs (8.9%) or lack of effectiveness (8.5%). One or more AE were
observed in 33.4% of patients; infections were observed in 12.5%. The most frequent AEs were by
system organ class were infections and infestations (12.5%). SAEs occurred in 7.3% of patients.
Malignancy (all causality) was reported in 0.6% of patients. There were 21 deaths (0.5%), of which the
most common causes (including patients with multiple causes listed) were infection (6 cases) and
malignancy (5 cases). Preliminary all-period (36-month) data were also presented. Malignancies
occurred in 1.6% of patients; gastric cancer in 0.2%, lung neoplasm malignant in 0.2%, breast cancer in
0.1% of patients; diffuse large B-cell lymphoma, ovarian cancer, uterine cancer, colon cancer, and
pancreatic carcinoma in 0.1% of patients each. The authors summarised that this interim analysis did
not reveal any new or unexpected safety signals compared with earlier clinical trials [#1515].

In a second poster based on the same PMS dataset, Tamura et al reported the incidence of serious
infarction events (SIEs), Pneumocystis jiroveci pneumonia (PCP), TB, and HZ among Japanese patients
with RA treated with tofacitinib. In the six-month observation period, the most frequently reported AE by
preferred term was HZ (3.7%), including one HZ meningoencephalitis (serious) and two disseminated
HZ (one serious; one non-serious). PCP was reported in 0.4% of patients (15 serious; one non-serious).
There were three TB cases (including one serious bone tuberculosis); no patients with TB had received
chemoprophylaxis with isoniazid before starting tofacitinib. At month 6, 3.3% patients had SIEs; most
common by preferred term were HZ (0.6%), pneumonia (0.6%), PCP (0.4%), and pneumonia bacterial
(0.3%). The authors concluded that the overall incidence rate of SIEs (6.81) was within the range of
rates reported in prior PMS studies of RA biologic treatment [#1516].
Dikranian et al reported an update to an earlier post-hoc analysis describing the frequency and duration
of the most commonly reported non-SAEs in patients with RA treated with tofacitinib 5 mg BID as
monotherapy or in combination with csDMARDs in Phase 3 and 3b/4 studies (ORAL: Step, Solo, Scan,
Sync, Standard, and Strategy). The analysis included 1976 patients receiving tofacitinib 5 mg BID
(monotherapy, n=122; combination therapy, n=559) and 681 patients receiving placebo.
Up to Month 3, the most frequently reported non-serious AEs headache, diarrhoea, nausea, vomiting,
dyspepsia, and upper abdominal pain. The frequency of non-SAEs was comparable for patients
receiving tofacitinib as monotherapy or in combination with csDMARDs. An incidence rate ≥10 was
observed for headache and diarrhoea in patients receiving tofacitinib 5 mg BID, and for nausea in
patients receiving placebo. Overall, non-serious, non-infectious AEs were mild or moderate and
self-limiting [#1537].
The safety and efficacy of tofacitinib in the Central and Eastern European (CEE) subpopulation of the
tofacitinib clinical program was evaluated by Vencovsky et al. A total of 1725 patients from CEE and
5296 patients from the rest of the world (ROW) were included in the safety analyses. TEAEs occurred in
80.5% of CEE patients and 88.9% of ROW patients; SAES occurred in 24.0% and 27.1% respectively;
the most common AE class was infections and infestations, occurring in 55.3% and 66.6%, respectively.
Improvements in composite efficacy measures were numerically greater for ROW versus CEE, whereas
changes in objective measures were more similar. The authors concluded that results were generally
consistent between CEE and ROW sub-populations [#1544].
Baricitinib safety
A poster by Hendricks and colleagues presented an analysis of CRP levels during bacterial infection in
RA patients treated with baricitinib or placebo, using pooled data from the BEAM, BUILD and BEACON
studies. A total of 36 and 30 patients treated with baricitinib and placebo had CRP values during
bacterial infection TEAEs of which 60% were urinary tract infections. In patients treated with baricitinib,
median CRP levels were 6.2 and 3.0 mg/L in the infection and infection-free period (p

Quality of life in RA
Boudhabhay and colleagues reported a systematic review and meta-analysis to compare the effect size
of JAKi and bDMARD versus sDMARDs on quality of life. The results showed better SF-36 PCS and
MCS at 12 weeks with JAKis and bDMARDs compared with sDMARDs; the magnitude of the
improvement over csDMARD in SF-36 PCS was +4.82 with JAKi and +3.99 with bDMARDs;
corresponding improvements in SF-36 MCS were +3.42 with JAKi and +2.99 with bDMARDs. Similar
confidence intervals were observed between JAKi and bDMARDs, suggesting a similar efficiency with
respect to both components of the SF-36 questionnaire [#1525].
Patient Outcomes, Preferences, and Attitudes: Patient-reported Outcomes
DMARDs and JAKis for pain and fatigue in RA
A systematic literature review performed by Ordriozola and colleagues examined data from clinical trials
comparing DMARDs or JAKis (restricted to baricitinib and tofacitinib) to placebo for pain and/or fatigue in
patients with RA. The authors identified 33 randomized controlled trials that evaluated pain VAS and
17 that investigated the FACIT-F score. The results showed that that the beneficial effects over placebo of
JAKi on pain and fatigue is not significantly different than biologic DMARDs, at least during the short-tomiddle
term, corresponding to the duration of clinical trials [#1401].
Measures and Measurement of Healthcare Quality
Tofacitinib for active PsA – a US health economic analysis
Bungey and colleagues report a decision model used to estimate and compare total costs, clinical
responses and per member per month costs between treatment sequences with and without tofacitinib
in patients with moderate-to-severely active PsA with a previous inadequate response to a csDMARD.
The model suggested that including tofacitinib in treatments for csDMARD-IR PsA patients is a costsaving
alternative to treatment sequences without tofacitinib. The inclusion of tofacitinib on formulary for
a payer insuring 1,000,000 individuals could reduce payer costs for PsA advanced therapies by more
than $5 million over two years [#1264].
Cytokines and Cell Trafficking
Preclinical study of a novel MK2 inhibitor
Using ex vivo models of immune mediated arthritis, Kragstrup et al showed that a small molecule MK2
inhibitor changed the secretory profile of synovial fluid mononuclear cells and decreased inflammatory
osteoclastogenesis. The results suggest a role for this MK2 inhibitor in attenuating inflammatory and
destructive arthritis [#983].
Innate immunity
Novel mechanism of action for tofacitinib
Marzaioli et al reported preclinical results suggesting a novel mechanism of action for tofacitinib in RA
and PsA. 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 [#1018].

Poster Sessions – ACR Poster Session C
Rheumatoid arthritis – Etiology and pathogenesis
Baricitinib reduces joint-related biomarkers in RA
A subset of results from 240 patients in the Phase 3 RA-BUILD study were reported by Thudium and
colleagues. Circulating levels of biomarkers from eighty patients per arm (placebo, baricitinib 2 mg or 4
mg) were analysed at baseline, Week 4, and Week 12 to identify markers that are affected by baricitinib
longitudinally. At Week 4, C1M was reduced by 21% from baseline by baricitinib 4 mg compared to
placebo (p

GS-9876 –Phase 2 study in patients with RA
Kivitz and colleagues presented Phase 2 study results of GS-9876, a novel, potent, highly selective, oral
inhibitor of SYK, in patients with active RA and prior IR to MTX or biologic anti-rheumatic drug. Patients
were randomized 1:1:1:1 to receive GS-9876 30 mg, GS-9876 10 mg, selective JAK inhibitor filgotinib
200 mg or matching placebo once daily for 12 weeks on a stable background of oral MTX. For DAS28-
CRP (primary endpoint), a statistically significant reduction from baseline at Week 12 was observed only
in patients receiving filgotinib as compared to placebo. AEs were reported across all groups (37.5% in
the combined GS-9876 arms, 38.1% in filgotinib arm, 40.9% in the placebo arm). No deaths or serious
AEs were reported. In summary, clinical efficacy of GS-9876 in RA was not observed, but GS-9876 was
safe and well-tolerated over a 12-week period in patients with active RA on MTX [#2518].
Upadacitinib efficacy and safety in RA
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 were presented by FitzGerald et al. 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 LDA within 12
weeks. The time taken to achieve various clinical responses was consistent irrespective of having an
inadequate response to csDMARD or bDMARD [#2523].
A second analysis of data from the SELECT-NEXT and SELECT-BEYOND trials was presented by van
Vollenhoven and colleagues. In csDMARD-IR and bDMARD-IR patients with RA, treatment responses at
12 weeks were observed in significantly higher proportions of patients in the upadacitinib group versus
placebo. Favourable effects with upadacitinib were seen in the composite scores (ACR50) and the
individual parameters, including PROs and acute-phase reactants [#2541].
The effect of upadacitinib on pain and morning stiffness in patients with RA in the SELECT-NEXT,
SELECT-BEYOND and SELECT-MONO randomized trials, were presented by Wells and colleagues.
Treatment with upadacitinib in combination with csDMARDs versus placebo resulted in significant and
rapid improvements in pain and morning stiffness across different RA patient populations including
csDMARD-IR and bDMARD-IR; similar improvements versus MTX were reported when UPA was
administered as monotherapy. For example, across all 3 trials, statistically significant least squares
mean percent changes from baseline to Weeks 12/14 in pain and duration of AM stiffness were reported
with upadacitinib 15 mg and 30 mg daily (except AM stiffness duration in BEYOND) compared with
placebo or MTX groups. Significantly more upadacitinib-treated patients (15 mg:
30-36%, 30 mg: 36-44%) reported no pain or mild pain at Weeks 12/14 compared with placebo or MTX
(14–15%). Improvements in upadacitinib-treated patients were evident as early as Week 2 [#2524].

Strand et al presented two posters on PROs with upadacitinib. The first poster reported analyses of the
SELECT-NEXT, SELECT BEYOND and SELECT-MONOTHERAPY studies. In general, change from
baseline in pain and HAQ-DI scores were marginally correlated with individual physician-derived measures
and moderate-to-high correlations were observed between pain, HAQ-DI and PtGA in both trials. Regression
analyses showed that improvements in individual disease assessments were associated with significant
improvements in pain at Week 12 and patients with improvement in composite measures were more likely to
report substantial improvements in pain. These findings support the use of PROs in randomised controlled
trials and highlight that their use as distinct parameters may provide additional insights into the true impact of
RA [#2546]. The second poster reported an analysis of data from 648 patients in the SELECT-
MONOTHERAPY trial only. Treatment with upadacitinib 15 mg or 30 mg as monotherapy for 14 weeks
resulted in statistically significant and clinically meaningful improvements in PROs compared with MTX,
including disease activity, pain, physical function, and HRQoL among MTX-IR patients [#2547].
Mohamed and colleagues presented analyses from two Phase 2b studies of upadacitinib in patients with
moderately to severely active RA who had an inadequate response to anti-TNF therapies (BALANCE I)
or MTX (BALANCE II). In 574 patients the percentage of subjects achieving ACR50, ACR70, LDA, and
clinical remission increased with increasing upadacitinib plasma exposures. Upadacitinib plasma
exposures associated with 6 mg BID to 12 mg BID using the immediate-release formulation (equivalent
to15 mg QD to 30 mg QD using the extended-release formulation, respectively) are predicted to achieve
near maximum efficacy in RA patients while having limited effects on NK cells, haemoglobin, LDL-C, and
HDL-C. Exposures higher than 12 mg BID are not predicted to result in additional efficacy benefits in
subjects with RA, but have the potential for greater effects on laboratory parameters. Results from these
analyses supported the evaluation of extended-release formulation 15 mg and 30 mg QD in Phase 3
trials in RA [#2542].
Baricitinib: efficacy in RA
Pope and colleagues presented data from a post-hoc analysis of the RA-BEACON trial. Baricitinib 2 mg
or 4 mg provided greater pain relief in bDMARD-IR patients with RA compared with placebo. Consistent
results were observed regardless of baseline pain or prior treatment history [#2531]
Rheumatoid Arthritis – Diagnosis, Manifestations, and Outcomes: Complications of Therapy,
Outcomes, and Measures
Tofacitinib safety
Soriano et al reported a prevalence of hepatic steatosis of 1.6% in 10212 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 [#2447].
The incidence of virus reactivation by tofacitinib in a cohort of patients with RA was reported by Urata
and colleagues. In 35 patients receiving a mean MTX dose of 7.5 mg per week, reactivation rates were
2.9, 8.6, 25.5 and 0% for cytomegalovirus, hepatitis B virus, varicella virus and Epstein Barr virus,
respectively [#2454].

Spondyloarthritis including Psoriatic Arthritis – Clinical: Treatment
Tofacitinib efficacy and safety in PsA
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, 2189 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 patients 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 [#2565].
A post-hoc analysis of the OPAL Broaden and OPAL Beyond studies was presented by Ogdie and
colleagues; this analysis examined baseline pain severity as a predictor of pain improvement following
treatment with tofacitinib 5 mg BID and included 236 patients with active PsA who were csDMARD-IR. In
patients with a baseline pain level of 90 mm, the predicted median time to achieve ≥30% pain
improvement was 39.3 days. Whereas, for a baseline pain level of 50 mm, the predicted median time to
achieve ≥30% pain improvement was 56.7 days. Therefore, the time to pain improvement was
dependent upon baseline pain severity, with lower pain scores at baseline associated with longer time to
improvement than higher pain scores. Patients with higher pain severity at baseline achieved clinically
meaningful pain improvements faster than patients with lower severity of pain [#2588].
De Vlam and colleagues presented a post-hoc analysis on data from 2 Phase 3 studies of tofacitinib in
patients with active PsA and inadequate response to ³1 csDMARD (OPAL Broaden) or to ³1 TNFi
(OPAL Beyond). 354 patients who were treated with tofacitinib 5 mg twice daily (BID) and placebo
advanced to tofacitinib 5 mg BID at Month 3 (PBO-tofacitinib), in combination with csDMARDs, were
included in this analysis. Current arthritis pain severity was reported by patients using a 100 mm visual
analog scale. Pain improvement was defined as the first post-baseline improvement of ≥30%
(meaningful change), ≥50% (substantial change), or ≥70% relative to baseline. Analyses showed that
patients receiving tofacitinib 5 mg BID achieved improvements in pain severity of 30–70% significantly
faster compared with patients in the PBO-tofacitinib group. The median time to ≥30% pain improvement
was 55 days in the tofacitinib 5 mg BID group and 106 days in the PBO-tofacitinib group (p=0.0132)
[#2594].
Systemic Lupus Erythematosus – Animal Models
Preclinical studies of filgotinib in lupus
Han et al reported preclinical findings with filgotinib, a JAK1 selective inhibitor, in a murine lupus model.
Filgotinib showed a dose-dependent decrease in proteinuria, a concomitant reduction in renal
inflammation, improved glomerular morphology and increased survival (versus placebo). An alteration of
splenic immune cell subsets affected by type I IFNs towards non-diseased levels was demonstrated for
filgotinib. Filgotinib also normalized renal expression of genes for structural damage, apoptosis,
complement system, and nucleic acid sensing. Importantly, among the 16
type I interferon signature genes measured, 12 showed a dose-responsive decrease with filgotinib
treatment [#2097].

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• Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Shiomi T, Yamada E. Efficacy and Safety of
the Novel Oral Janus Kinase (JAK) Inhibitor, Peficitinib (ASP015K), in a Phase 3, Double-Blind, Placebo-Controlled, Randomized Study of Patients
with RA Who Had an Inadequate Response to Methotrexate [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 888.
• Tamura N, Kuwana M, Atsumi T, Takei S, Harigai M, Fujii T, Matsuno H, Mimori T, Momohara S, Yamamoto K, Takasaki Y, Nomura K, Endo Y,
Hirose T, Morishima Y, Sugiyama N, Yoshii N, Takagi M. Malignancy in Japanese Patients with Rheumatoid Arthritis Treated with Tofacitinib:
Interim Analysis of All-Case Post-Marketing Surveillance [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 1515.
• Tamura N, Kuwana M, Atsumi T, Takei S, Harigai M, Fujii T, Matsuno H, Mimori T, Momohara S, Yamamoto K, Takasaki Y, Nomura K, Endo Y,
Hirose T, Morishima Y, Sugiyama N, Yoshii N, Takagi M. Infection Events in Japanese Patients with Rheumatoid Arthritis Treated with Tofacitinib:
Interim All-Case Post-Marketing Surveillance [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 1516.
• Tanaka Y, Takeuchi T, Tanaka S, Kawakami A, Iwasaki M, Song YW, Chen YH, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Shiomi T, Yamada E.
Efficacy and Safety of the Novel Oral Janus Kinase (JAK) Inhibitor, Peficitinib (ASP015K), in a Phase 3, Double-Blind, Placebo-Controlled,
Randomized Study of Patients with RA Who Had an Inadequate Response to Dmards [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract
887.
• Taylor PC, Downie B, Zhuo L, Gindin Y, Tarrant J, Liu J, Galien R, Mirza AM. The JAK1-Selective Inhibitor Filgotinib Reverses the Disease-
Associated Transcriptional Profile Found in the Blood of Patients with Active Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl
10): Abstract 2517.
• Taylor PC, Tanaka Y, Cardoso A, Zhong J, Chen YF, Workman JL, Morales LDC, Schiff M. Baricitinib: Early Vs. Delayed Start in Patients with
Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 546.
• Teitsma XM, Jacobs JWG, Concepcion AN, Pethö-Schramm A, Borm ME, van Laar J, Bijlsma JWJ, Lafeber FP. Sustained Drug-Free Remission in
Early RA Following Methotrexate-Based Strategy: Role of the JAK-STAT Pathway [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 2899.
• Thudium CS, Bay-Jensen AC, Cahya S, Dow ER, Karsdal MA, Koch AE, Zhang W, Benschop RJ. Effect of Baricitinib on Joint-Related Biomarkers in
Patients with Moderate-to-Severe Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 2035.
• Urata Y. Virus Reactivation Rate in Rheumatoid Arthritis Using Tofacitinib [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 2454.
• van Vollenhoven R, Dore RK, Chen K, Camp HS, Enejosa JJ, Shaw T, Suboticki J, Hall S. Impact of 12-Weeks of Upadacitinib Treatment on
Individual and Composite Disease Measures in Patients with Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic or Biologic
Dmards [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 2541.
• van Vollenhoven R, Takeuchi T, Pangan AL, Friedman A, Mohamed ME, Chen S, Rischmueller M, Blanco R, Xavier RM, Strand V. A Phase 3,
Randomized, Controlled Trial Comparing Upadacitinib Monotherapy to MTX Monotherapy in MTX-Naïve Patients with Active Rheumatoid Arthritis
[abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 891.
• Vencovsky J, Badurski J, Forejtová Š, Lukáčová O, Stanislavchuk M, Yaneva-Bichovska D, Shi H, Vasilescu R, Lukic T, Kabina M. Tofacitinib
Safety and Efficacy in the Treatment of Rheumatoid Arthritis in a Central/Eastern European Subpopulation [abstract]. Arthritis Rheumatol. 2018; 70
(suppl 10): Abstract 1544.
• Wallace DJ, Furie R, Tanaka Y, Kalunian KC, Mosca M, Petri M, Dorner T, Cardiel MH, Bruce IN, Gomez E, DeLozier AM, Janes J, Linnik MD, de
Bono S, Silk ME, Hoffman RW. Baricitinib in Patients with Systemic Lupus Erythematosus: Results from a Phase 2, Randomized, Double-Blind,
Placebo-Controlled Study [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 970.
• Weinblatt M, Taylor PC, Burmester GR, Saifan C, Walls CD, Issa M, Rooney TP, Takeuchi T. Cardiovascular Safety – Update from up to 6 Years of
Treatment with Baricitinib in Rheumatoid Arthritis Clinical Trials [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 2815.
• Weinblatt ME, Taylor PC, Keystone EC, Ortmann RA, Issa M, Xie L, de Bono S, Tanaka Y. Efficacy and Safety of Switching from Adalimumab to
Baricitinib: Long-Term Data from Phase 3 Extension Study in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10):
Abstract: 886.

• Wells AF, Lee YC, Tundia N, Suboticki J, Chen K, Friedman A, Strand V. Effect of Upadacitinib on Pain and Morning Stiffness in Patients with
Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic or Biologic Disease-Modifying Anti-Rheumatic Drugs [abstract]. Arthritis
Rheumatol. 2018; 70 (suppl 10): Abstract 2524.
• Yun H, Xie F, Chen L, Curtis JR. Risk of Venous Thrombotic Events in Rheumatoid Arthritis Patients Initiating Tofacitinib or Adalimumab [abstract].
Arthritis Rheumatol. 2018; 70 (suppl 10): Abstract 224.