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EULAR 2017 IL6 Review

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Enhancing knowledge of the clinical<br />

importance of cytokine signalling<br />

The Cytokine Signalling Forum<br />

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<strong>EULAR</strong> <strong>2017</strong><br />

Conference Highlights<br />

Interleukin 6 Science<br />

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Chairman’s Welcome<br />

<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Dear CSF Member,<br />

Thank you for your continued support of the Cytokine Signalling Forum. We are now in our fourth year, and continue to strive to bring<br />

you the most up-to-date and interesting data in cytokine signalling. To that end, I am delighted to share with you our pick of the <strong>EULAR</strong><br />

highlights for <strong>2017</strong>. We have identified the most interesting and impactful abstracts being presented at this year’s meeting on both cytokine<br />

signalling and IL-6. I have also selected my ‘Chairman’s picks’: those abstracts that I feel are the most significant at this year’s congress.<br />

Cytokine Signalling<br />

Again, this year there is an interesting range of both basic and clinical science. There are several baricitinib posters covering durability<br />

and maintenance of efficacy [FRI0096], switching to monotherapy [SAT0058], and dose reduction [SAT0072]. The possibility of an<br />

anti-inflammatory biomarker profile in patients treated with filgotinib monotherapy is examined [THU0182], and the results of the DARWIN-3<br />

open label extension study up to 144 weeks are presented in Thursday’s poster session and tour [THU0173].<br />

Tofacitinib posters in RA concentrate on long-term safety and efficacy over eight years [THU0197] as well as an examination of<br />

cardiovascular risk factors [SAT0686], and safety and efficacy in patients with an inadequate response to conventional synthetic or biologic<br />

DMARDs [THU0185]. Real-world tofacitinib drug-retention data are also shared as a poster from the Swiss SCQM registry [THU0174];<br />

and real-world tofacitinib monotherapy data from the US CORRONA registry as an oral presentation [OP0022]. Three further oral<br />

presentations on Thursday and Friday will share exciting new data from the Phase 3 tofacitinib studies in psoriatic arthritis [OP0202;<br />

OP0216] as well as long-term effectiveness of live zoster vaccine in patients with RA, subsequently treated with tofacitinib [OP0230].<br />

IL-6<br />

Several abstracts showcase key data from the clinical programmes of sarilumab, sirukumab and tocilizumab.<br />

There are three key presentations on sarilumab, including patient-reported (PROs) from two Phase 3 studies in RA [FRI0240], and efficacy<br />

and patient-reported benefits of sarilumab monotherapy versus adalimumab monotherapy in the MONARCH study [SAT0202; OP0102].<br />

Sirukimab posters focus on Phase 3 data in RA, with efficacy and safety from the SIRROUND-T study [FRI0214], analyses of health-related<br />

quality of life and work productivity from SIRROUND-D and -T, respectively [FRI0246; FRI0251], and an integrated safety analysis of the<br />

SIRROUND programme [SAT0194].<br />

Tocilizumab oral presentations examine tapering and dose reduction strategies [OP0104] as well as the long-term safety profile seen in<br />

clinical trials and post-marketing populations [OP0105]. Tocilizumab posters look at real-world data, with clinical remission in the TOSPACE<br />

trial [SAT0183], and a pooled analysis of Phase 4 data across 22 countries [SAT0199].<br />

The following pages provide an overview of these topics and highlight my ‘Chairman’s picks’. Once again, thank you for your support and<br />

I hope you enjoyed <strong>EULAR</strong> <strong>2017</strong>!<br />

Yours,<br />

Prof. Iain McInnes


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Highlights from <strong>EULAR</strong> <strong>2017</strong>: Interleukin 6 (IL-6)<br />

During the <strong>EULAR</strong> <strong>2017</strong> annual meeting, many presentations and posters reported on<br />

IL-6 and related drugs. This document reviews the highlights.<br />

A separate highlights document covering cytokine signalling and related drugs is<br />

also available.<br />

Sarilumab<br />

Sarilumab is a human monoclonal antibody that blocks the IL-6 receptor. There were<br />

several presentations showcasing Phase 3 data from the clinical trial programme in RA.<br />

Clinical efficacy<br />

Fleischmann, et al. shared the results of dose reduction in the EXTEND open-label<br />

extension study, where investigators could reduce sarilumab from 200 mg Q2W to 150<br />

mg Q2W in patients with absolute neutrophil count (ANC) ≥0.5–1.0 Giga/L, platelet<br />

count ≥50–100 Giga/L, or alanine aminotransferase (ALT) ≥3–5-times the upper limit of<br />

normal (ULN). Dose reductions occurred in 66 patients, and most showed improvement<br />

in laboratory abnormalities and could continue treatment. Improvements in signs and<br />

symptoms of RA and physical function were maintained after dose reduction [SAT0212].<br />

Burmester, et al. presented results from the Phase 3 MONARCH study of sarilumab<br />

versus adalimumab monotherapy. At Week 24, sarilumab was superior in change from<br />

baseline in DAS28-ESR, and sarilumab-treated patients achieved significantly higher rates<br />

of ACR20, health assessment questionnaire disability index (HAQ-DI) and clinical disease<br />

activity index (CDAI). Results were generally consistent across subgroups, although the<br />

magnitude of treatment effect for DAS28-ESR was greater in patients with lower body<br />

mass index (BMI) and higher baseline C-reactive protein (CRP) [SAT0202].<br />

In a post hoc analysis, Genovese, et al. examined the association between clinical<br />

response, radiographic progression and functional response in the MOBILITY study.<br />

More sarilumab- than placebo-treated patients achieved remission or no x-ray<br />

progression. The authors also found that achieving low disease activity, remission, or<br />

absence of radiographic progression was associated with overall greater improvements<br />

in physical function [FRI0242].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Patient-reported outcomes<br />

Gossec, et al. presented details on the use of the RA impact of disease (RAID) scale<br />

in 2 Phase 3 trials. Sarilumab was superior to placebo and adalimumab at Weeks 12<br />

and 24 for RAID total score, and the effect of sarilumab was consistent across all 7<br />

individual RAID domains, except for sleep difficulties versus placebo in the TARGET trial.<br />

The effects of placebo were highest on pain; the effects of sarilumab were lowest on<br />

emotional well-being and coping. The authors concluded that sarilumab as monotherapy<br />

or in combination with conventional synthetic disease-modifying antirheumatic drugs<br />

(csDMARDs) reduced the impact of RA on patients’ lives to a greater extent than<br />

adalimumab monotherapy or placebo plus csDMARDs [FRI0240].<br />

An oral presentation from Strand, et al. looked at patient-reported outcomes (PROs) in the<br />

MONARCH study, which found that improvements from baseline to Week 24 were greater<br />

with sarilumab versus adalimumab across a number of PROs, including Patient Global<br />

Assessment of Disease Activity (PtGA), Pain, HAQ-DI, Morning Stiffness, RAID and the<br />

RA-specific Work Productivity Survey (WPS-RA) global scores [OP0102].<br />

Safety<br />

In Burmester, et al., reported above, the incidence of AEs was similar in both groups,<br />

including infections and serious infections. The most common AEs were neutropenia and<br />

injection site erythema (sarilumab), and headache and worsening of RA (adalimumab)<br />

[SAT0202].<br />

Gabay, et al. presented on the effects of sarilumab or adalimumab monotherapy on<br />

circulating biomarkers associated with acute-phase response, bone resorption, and<br />

cardiovascular (CV) risk in patients from MONARCH. A significant difference in RANKL<br />

was observed at Weeks 2 and 24: numerically, RANKL decreased after sarilumab and<br />

increased after adalimumab treatment. Significantly greater reductions in lipoprotein A,<br />

serum amyloid A (SAA), and CRP were observed at Weeks 12 and 24. The difference in<br />

osteoprotegerin between groups was significant at Week 2 only [FRI0227].<br />

Basic science<br />

Damask, et al. collected DNA from patients in MOBILITY and found a strong association<br />

between rs6742078 and bilirubin levels in patients with RA treated with sarilumab –<br />

consistent with previous observations in tocilizumab-treated patients. The authors<br />

concluded that these findings suggest that sarilumab-related increases in bilirubin levels<br />

are likely benign and caused by common genetic variation in UGT1A1, and are not due to<br />

underlying liver injury [FRI0228].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Paccard, et al. compared gene expression patterns in circulating blood cells after<br />

treatment with sarilumab versus placebo in patients from MOBILITY and TARGET.<br />

They found that sarilumab may decrease thrombosis-related gene expression in<br />

circulating immune cells, but additional analysis of the serum levels of thrombosis risk<br />

proteins is needed to test the hypothesis that sarilumab treatment decreases levels of<br />

thrombosis risk factors [SAT0192].<br />

Sirukumab<br />

Sirukumab is a selective, high-affinity human monoclonal antibody directed against the<br />

IL-6 cytokine. It is currently being developed for RA and other diseases. There was a<br />

focus on PROs and safety in the clinical development programme.<br />

Clinical efficacy<br />

Tanaka, et al. presented Week 52 results of the Phase 3 SIRROUND-T study in 878<br />

patients. Improvements were maintained through Week 52 with no dose response<br />

[FRI0214].<br />

Patient-reported outcomes<br />

Strand, et al. performed a post hoc analysis looking at health-related quality of life<br />

(HRQoL) in 1670 patients in SIRROUND-D. At Week 24, sirukumab resulted in significantly<br />

greater mean improvements versus placebo in the 36-item Short Form Questionnaire<br />

(SF-36) physical and mental component scores (PCS and MCS) more than the minimal<br />

clinically important difference (MCID). Significantly greater proportions of patients also<br />

reported clinically meaningful improvements in fatigue with sirukumab versus placebo<br />

[FRI0246].<br />

A second PRO poster from Strand, et al. focused on SIRROUND-D in TNF-IR patients.<br />

Sirukumab treatment resulted in greater and clinically meaningful improvements in HRQoL<br />

versus placebo, with results that met or exceeded population normative values. Similar<br />

results were seen for sirukumab at dosages of 50 mg Q4W and 100mg Q2W [SAT0182].<br />

Tanaka, et al. reported improvements in work productivity and general health status in<br />

TNF-IR patients in the SIRROUND-T study. At Week 24, scores on the Work Limitations<br />

Questionnaire (WLQ), EQ-5D and health state scales improved significantly for sirukumab<br />

versus placebo. Improvements were maintained through Week 52 for both sirukumab<br />

doses [FRI0251].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

A post hoc analysis by Sun, et al. examined the effect of sirukumab on depressive<br />

symptoms in SIRROUND-D and SIRROUND-T. At baseline, 19% and 22% of patients<br />

were classified as having prevalent depressed mood and anhedonia (PDMA) in the two<br />

studies, respectively. Sirukumab significantly improved depressive symptoms by Week<br />

8 in these patients, compared with placebo. Within the sirukumab group, the reduction<br />

in depressive symptoms remained significant after adjusting for changes in RA activity<br />

and in ACR50 non-responders at Week 8; differences in improvements between the<br />

sirukumab and placebo group reduced to trends. It is thought that anti-IL-6 treatment<br />

may help to alleviate depressive symptoms even after adjusting for changes in disease<br />

activity [THU0130].<br />

Safety<br />

In the Phase 3 SIRROUND-T study presented by Tanaka, et al., AEs were reported for<br />

79.6% and 81.3% of patients in the combined sirukumab 50 mg Q4W and 100 mg<br />

Q2W groups, respectively, and SAEs for 14.2% and 13.2%, respectively, through Week<br />

52. Injection-site reactions and ALT increases were the most commonly reported AEs<br />

[FRI0214].<br />

Takeuchi, et al. assessed the incidence of neutropenia from completed and ongoing<br />

SIRROUND clinical studies in 2926 patients. Across the Phase 3 studies, there was<br />

no dose effect of sirukumab on neutropenia, and the use of DMARDs did not have an<br />

apparent effect on neutropenia. The majority of Grade 4 neutropenia with sirukumab was<br />

not associated with infections [FRI0252].<br />

An integrated safety analysis from Aletaha, et al. looked at data from 2926 sirukumab<br />

patients for up to 3.4 years in the Phase 3 SIRROUND trials. Up to Week 18 there were<br />

more AEs, AEs leading to discontinuation, and SAEs with sirukumab versus placebo,<br />

with cumulative rates of SAEs remaining constant over time. In general, no dose effect<br />

was observed in the 18-week or long-term analysis. Mortality and serious infections were<br />

similar across treatment groups through 18 weeks and in the long-term analysis. Rates<br />

of gastrointestinal perforations and malignancies were low and similar; major adverse<br />

cardiovascular event (MACE) rates were similar through 18 weeks, and numerically<br />

higher with sirukumab 50 mg Q4W versus sirukumab 100 mg Q2W over the long term<br />

[SAT0194].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Basic science<br />

Dasgupta, et al. gave an oral presentation on the effect of sirukumab plus methotrexate<br />

(MTX) on circulating biomarkers of joint destruction using serum samples from 200<br />

patients in SIRROUND-D. Overall, sirukumab 50 mg Q4W in combination with MTX<br />

inhibited radiographic progression and strongly inhibited biomarkers of joint and tissue<br />

destruction while enhancing markers of bone formation. The authors conclude these data<br />

suggest that sirukumab may actively suppress inflammatory pathways implicated in joint<br />

destruction in RA [OP0103].<br />

Anaemia of chronic disease is common in RA and may be detrimental to QoL and longterm<br />

health. Loza, et al. conducted a post hoc analysis of haematology measures in 4<br />

Phase 3 studies, showing that sirukumab consistently reduced the prevalence of anemia<br />

to a greater extent than that observed for placebo. These effects were independent of the<br />

extent of improvement in RA disease activity, suggesting additional benefits of sirukumab<br />

beyond clinical response. The authors postulate that by inhibiting IL-6, sirukumab<br />

may decrease key iron-regulatory proteins and shift homeostasis towards an increase<br />

in the pool of iron available for red blood cells, thus ameliorating anaemia of chronic<br />

inflammation [FRI0243].<br />

Tocilizumab<br />

As in previous years, there continued to be large numbers of presentations on the IL-6R<br />

inhibitor tocilizumab, with a focus on real-world data in RA, as well as efficacy data in<br />

new indications.<br />

Clinical efficacy in RA<br />

Choy, et al. performed a pooled analysis of Phase 4 studies in 1804 patients to evaluate<br />

the efficacy and safety of subcutaneous tocilizumab 162 mg QW as monotherapy<br />

or in combination with csDMARDs. Subcutaneous administration demonstrated<br />

convincing and comparable efficacy compared to mono- and combination therapy<br />

previously observed with intravenous administration of tocilizumab. The safety profile of<br />

subcutaneous tocilizumab was consistent with the known safety profile [SAT0199].<br />

In a publication-only abstract, Fautrel, et al. presented the 24-week results of TOSCA,<br />

a Phase 3b study in France also looking at subcutaneous administration in 139 patients.<br />

At 6 months, subcutaneous tocilizumab demonstrated comparable efficacy, safety and<br />

steroid-sparing results in mono- and combination therapy, consistent with the known<br />

profile of intravenous tocilizumab [AB0395].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Mueller, et al. presented a sub-analysis of ACT-SURE study, looking at 107 patients<br />

treated with tocilizumab. No differences in ACR20/50/70/90 response rates were<br />

observed between monotherapy or combination therapy groups at Week 24. The median<br />

time to low disease activity was significantly shorter in patients treated with combination<br />

therapy than monotherapy [FRI0247].<br />

Patient-reported outcomes in RA<br />

PROs from BREVACTA and SUMMACTA were investigated by Strand, et al. In BREVACTA,<br />

significantly more patients who received subcutaneous tocilizumab reported scores<br />

greater than MCID for all PROs at Week 12 compared with those receiving placebo. In<br />

SUMMACTA, similar proportions of patients who received subcutaneous or intravenous<br />

tocilizumab reported scores greater than the MCID in all PROs at Week 24. The proportion<br />

of patients who reported scores greater than normative values was comparable between<br />

the subcutaneous or intravenous groups across all PROs [FRI0253].<br />

Teitsma, et al. reported on QoL from the U-ACT-EARLY trial in 317 patients, finding<br />

significantly greater improvements in PCS over time in patients initiating treatment with<br />

tocilizumab. For the SF-36 MCS, no significant differences over time were noted between<br />

the treatment arms. A significantly higher proportion of patients initiating treatment<br />

with tocilizumab achieved greater than MCID in SF-36 PCS at Week 12 and Week<br />

52 compared with those initiating treatment with MTX: 76%/89% and 73%/89% for<br />

tocilizumab alone and in combination with MTX versus 59%/73% for MTX alone at Weeks<br />

12/52, respectively [SAT0218].<br />

Caetano, et al. evaluated the relationship between PROs and fatigue in 18 patients, and<br />

whether fatigue influences disease remission definition in patients with RA treated with<br />

tocilizumab. According to DAS28-CRP, 44% of patients were in remission, 22% had<br />

low disease activity and 33% had moderate activity. ACR/<strong>EULAR</strong> Boolean criteria for<br />

remission were fulfilled by 17% of patients; patient global assessment (PGA) was the only<br />

reason for not achieving remission in 56%. In all patients, PGA correlated with higher<br />

fatigue scores, and in the group of patients not fulfilling Boolean remission, a similar<br />

correlation between PGA and higher fatigues scores was found. In the sub-group of<br />

patients in which PGA was the only factor for not achieving Boolean remission, there was<br />

a significant correlation between PGA and fatigue scores that was not present in the other<br />

patients [AB0238].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Factors influencing the prescription of tocilizumab alone or in combination with DMARDs<br />

in a real-life setting were examined in a pooled analysis of 3 observational studies by<br />

Saraux, et al. 1494 patients were analysed at inclusion. Tocilizumab was initiated as<br />

monotherapy in 36.4% and as combination therapy in 63.6%. Variables associated with a<br />

monotherapy prescription were age ≥65 years, number of previous bDMARDs, use/dose<br />

of steroids, ESR/CRP values, VAS global activity (physician and patient), pain VAS and<br />

HAQ-DI [SAT0189].<br />

Clinical efficacy in polymyalgia rheumatica<br />

Ueno, et al. presented the results of tocilizumab therapy in nine patients with polymyalgia<br />

rheumatic (PMR) who were resistant or intolerant to glucocorticoids and MTX.<br />

After treatment with tocilizumab, five patients were able to discontinue glucocorticoids,<br />

and four were able to withdraw MTX. Drug-free remission was achieved by two patients,<br />

suggesting tocilizumab may be an option in patients with severe PMR resistant to current<br />

therapies [FRI0313].<br />

In a publication-only abstract, Amano, et al. also looked at tocilizumab in PMR, examining<br />

monotherapy in 13 patients. Tocilizumab was effective in nine patients, although<br />

response was not as rapid as that seen with glucocorticoids. The authors conclude that<br />

tocilizumab monotherapy may be a good alternative for elderly PMR patients with various<br />

comorbidities [AB0984].<br />

Clinical efficacy in giant cell arteritis<br />

Domínguez-Casas, et al. assessed clinical efficacy in 31 patients with giant cell arteritis<br />

(GCA) in a retrospective multi-centre open-label study. The authors reported rapid and<br />

sustained improvement in patients with refractory GCA and/or with unacceptable side<br />

effects related to corticosteroids [FRI0336].<br />

Clinical efficacy in juvenile localised scleroderma<br />

A poster presentation from Foeldvari, et al. assessed the efficacy of tocilizumab in<br />

11 patients with juvenile localised scleroderma (jlSc) with non- or partial response to<br />

conventional therapy. Therapy success was reflected by a decreased Modified Localised<br />

Scleroderma Skin Severity Index (mLoSSI) in eight patients, and a decrease in the<br />

Localised Scleroderma Skin Damage Index (LoSDI) in 6. No new lesions occurred during<br />

treatment and no increase in the facial atrophy occurred in patients with Parry Romerg<br />

subtype [THU0511].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Clinical efficacy in juvenile idiopathic arthritis<br />

Mallalieu, et al. examined the use of 12 mg/kg tocilizumab for 11 patients under the age<br />

of 2 with systemic juvenile idiopathic arthritis (sJIA). Drug exposure fell within the range<br />

of the previous trial in sJIA patients over the age of 2 years. The authors concluded that<br />

this study provides evidence that tocilizumab is effective in this patient group, and has a<br />

similar AE safety profile, although there was a higher incidence of serious hypersensitivity<br />

events and suspected macrophage activation syndrome (MAS). [OP0197].<br />

Reaults from a study of subcutaneous tocilizumab in 52 patients with polyarticularcourse<br />

JIA (pcJIA) was presented in a poster by De Benedetti, et al. JADAS-71 generally<br />

improved, with trends consistent with those for intravenous tocilizumab. Infections were<br />

the most common AE, reported in 36 patients, and 2 serious infections occurred in one<br />

patient. Injection-site reactions occurred in 15% of patients weighing less than 30 kg,<br />

and in 44% of those weighing over 30 kg [THU0503].<br />

Clinical efficacy in uveitis<br />

Vegas-Revenga, et al. presented two posters on the clinical efficacy of tocilizumab in<br />

uveitis. The first looked at 25 patients with uveitis associated with JIA. All outcome<br />

variables showed rapid and sustained improvement after follow-up of up to 3 years,<br />

and a reduction in prednisone dose was observed. Main AEs were severe autoimmune<br />

thrombocytopenia, autoimmune anaemia and thrombocytopenia, pneumonia, viral<br />

conjunctivitis and bullous impetigo (one patient each) [THU0526].<br />

The second poster examined the use of tocilizumab in 25 patients with refractory and<br />

severe uveitic cystoid macular oedema. Tocilizumab provided rapid efficacy, with no side<br />

effects after 1 month of treatment [THU0567].<br />

Clinical efficacy in Still’s disease<br />

Kondo, et al. presented 52-week data from a single-centre open-label study of<br />

tocilizumab in seven patients with adult-onset Still’s disease. White blood cell counts,<br />

CRP and serum ferritin level decreased significantly at Month 7, and fever, arthralgia<br />

and eruption were improved. Five patients completed the 7-month course and had no<br />

symptoms at Month 7. There were no SAEs during the trial [THU0577].<br />

Structural efficacy in RA<br />

Möller, et al. shared results from the 285 patients in the ACT-RAY trial. They found that<br />

anaemia at baseline was a strong predictor of radiographic progression. Furthermore, in<br />

contrast to DAS28, anaemia remained a significant predictor of modified Total Sharp<br />

Score (mTSS) for up to 2 years on tocilizumab [FRI0225].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

In a 2-year follow-up of a registry study, Kanayama, et al. showed that tocilizumab can<br />

suppress the radiographic progression of cervical lesions in patients with RA [FRI0254].<br />

Structural efficacy in osteoarthritis<br />

Huerta, et al. reported on the use of tocilizumab for erosive osteoarthritis of the hands in<br />

24 patients that showed improvements in pain, morning stiffness and functional limitation.<br />

Laboratory results also showed decreased ESR, CRP, and IL-6 levels. The authors<br />

concluded that intravenous tocilizumab may be useful to control clinical manifestations of<br />

erosive osteoarthritis of the hands, although more precise studies are needed to evaluate<br />

the improvement of the cartilaginous matrix [SAT0524].<br />

Safety in RA<br />

Mohan, et al. gave an oral presentation reviewing long-term safety data from completed<br />

clinical trials and the post-marketing safety database. In 7647 tocilizumab-treated<br />

patients with RA from clinical trials – constituting 22 394 patient-years of exposure –<br />

the overall rate of SAEs was 14.16 per 100 patient-years. In the global post-marketing<br />

population of 606 937 patients, the overall spontaneous reporting rate of AEs of special<br />

interest was 9.37 cases per 100 patients, consistent in each 6-month period over the<br />

7-year duration [OP0105].<br />

The incidence of melanoma in tocilizumab was investigated by Gale, et al. In the clinical<br />

trial setting, 4 qualifying cases were identified among 7093 patients with RA treated with<br />

tocilizumab, giving a standardised incidence ratio (SIR) comparable to that of the general<br />

population. In the post-marketing setting, the number of observed reports of melanoma<br />

was comparable to the expected number of cases in Europe and Japan, and fewer than<br />

expected in North America. The exception was Australia, where the SIR indicated more<br />

than the expected number of cases compared with the general population in that region<br />

[FRI0248].<br />

Specker, et al. used data from ICHIBAN to characterise the occurrence of anaemia in<br />

patients with RA treated with tocilizumab. As early as 4 weeks’ treatment, the proportion<br />

of patients with anaemia improved to 12.1% (men) and 12.7% (women); after 104 weeks,<br />

there were further reductions to 7.4% (men) and 8.4% (women) [SAT0193].<br />

Fernández-Díaz, et al. looked at 12 patients with interstitial lung disease related to RA.<br />

Tocilizumab was prescribed as monotherapy (n=8) or in combination with other DMARDs<br />

(n=4). They found that dyspnea and pulmonary involvement remained stable in many<br />

patients [THU0134].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Byrne, et al. reported on the discontinuation rates for tocilizumab at one teaching hospital<br />

in the UK. Of 132 patients, one-third discontinued: five due to primary and 10 due to<br />

secondary inefficacy, and 27 due to AEs, including 8 cases of recurrent infections,<br />

5 abnormal LFT results, 4 malignancies and 3 cases of rash. A logistic regression model,<br />

including gender, smoking status, disease duration, DMARD use, steroid treatment and<br />

number of prior bDMARDS was constructed to examine association with treatment<br />

discontinuation. Of these factors, disease duration and number of previous bDMARDS<br />

were weakly associated with persistence of tocilizumab; there was no association of<br />

concomitant DMARD or steroid treatment with discontinuation either due to lack of<br />

efficacy or AEs. There were no cases of infusion reaction, diverticular perforation or<br />

reactivation of tuberculosis [SAT0198].<br />

In a publication-only abstract, Talotta, et al. reported a small case series of five patients<br />

with RA with evident worsening of subcutaneous nodulosis during treatment with<br />

intravenous tocilizumab. [AB0413].<br />

Real-world efficacy in RA<br />

In a publication-only abstract, Harrold, et al. discussed the comparative effectiveness<br />

of tocilizumab monotherapy compared to TNFi in combination with varying doses of<br />

MTX in patients with RA enroled in the CORRONA registry. They found that tocilizumab<br />

monotherapy was as effective as TNFi plus MTX, regardless of MTX dose, for improving<br />

disease activity in patients with prior TNFi exposure. These data suggest that tocilizumab<br />

monotherapy is an effective treatment option for patients with RA who cannot tolerate or<br />

prefer not to use MTX [AB0407].<br />

Frisell, et al. compared effectiveness of abatacept, rituximab, tocilizumab and TNFi in<br />

ARTIS. Tocilizumab was prescribed as first bDMARD in 202 patients, and as switch from<br />

TNFi in 320. Despite channelling of older and sicker individuals to non-TNFi bDMARDs,<br />

treatment outcomes were in general better in these groups, particularly for tocilizumab<br />

and rituximab. In interpreting this, the authors note that the risk of residual confounding<br />

should be remembered, and that this study did not include safety or long-term outcomes<br />

[FRI0213].<br />

Data from the LOHREN registry were also presented. Favalli, et al. showed comparative<br />

efficacy and retention rates of first-line tocilizumab or TNFi used in combination with MTX.<br />

Of 591 patients, 61 received tocilizumab. No significant differences emerged in the 6- or<br />

12-month retention rates. Clinical remission was achieved in 59% of tocilizumab-treated<br />

patients versus 33% for TNFi [FRI0215].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Specker, et al. performed an interim analysis of ICHBAN, a German non-interventional<br />

study, to assess the effectiveness of intravenous tocilizumab with respect to smoking<br />

status. Tocilizumab treatment over 2 years resulted in improvements in all disease activity<br />

parameters. Contrary to the experience with csDMARDs and TNFi, smokers appear to<br />

benefit from tocilizumab to the same extent as non- and ex-smokers [AB0396].<br />

Nakabo, et al. looked at clinical remission in 400 patients. Use of ultrasound revealed<br />

that clinical remission can be overestimated by using criteria based on baseline simplified<br />

disease activity index (SDAI) or DAS28-ESR. They concluded that, for patients receiving<br />

tocilizumab, CDAI-based criteria for clinical remission are more reliable than other<br />

measures [FRI0673].<br />

Real-life efficacy and safety were also evaluated by Pomponio, et al. In 100 patients,<br />

tocilizumab was found to be effective and well tolerated. There were no unexpected AEs.<br />

The authors also found that the retention rate was not affected by the administration<br />

route, and that many real-life patients can safely shift across different administration<br />

modalities [AB0400].<br />

Hara, et al. studied the use of residual Power Doppler (PD) signals for assessing synovitis<br />

in<br />

CRP-negative patients with RA treated with bDMARDs. They found that patients<br />

who achieved clinical remission had residual PD signals. Furthermore, patients with<br />

tocilizumab-induced remission had more residual PD signals compared with TNFi- or<br />

abatacept-induced remission. They suggest that more strict criteria of clinical remission<br />

may reduce residual PD signals in patients treated with tocilizumab [SAT0083].<br />

A prospective, observational, single-centre study by Ruiz-Esquide, et al. looked at<br />

therapeutic drug monitoring in tocilizumab patients. The authors found that tocilizumab<br />

serum concentrations do not differ between 8- or 6 mg/kg regimens. Therefore, they<br />

suggest a maintenance dose of<br />

6 mg/kg would be appropriate for most patients with RA [SAT0184].<br />

Kunishita, et al. reviewed 92 patients from a single centre to compare continuation rates<br />

of tocilizumab and identify predictive factors for good response. They found that patients<br />

with RA who achieved a good response at 6 months showed higher continuation rates<br />

than others. This study also suggested that low usage of previous bDMARDs and low<br />

CDAI at baseline are predictive factors for good response [AB0416].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Retention was also reviewed by Lauper, et al. on behalf of the TOCCERA collaboration.<br />

Of 4748 bDMARD eligible-patients, 585 received tocilizumab monotherapy and 4163<br />

received TNFi combination therapy. Patients who received tocilizumab monotherapy<br />

were older and had longer disease duration, more previous bDMARDs and less<br />

glucocorticosteroid use at baseline. Crude median retention for tocilizumab monotherapy<br />

was 1.82 years compared with 1.54 years for TNFi combination. Reasons for discontinuation<br />

differed: tocilizumab monotherapy was stopped more frequently for ineffectiveness, and<br />

TNFi combination was stopped more frequently for safety issues [SAT0206].<br />

Kikuchi, et al. compared retention rates in 68 elderly patients with RA who cannot tolerate<br />

MTX. Cumulative retention rates were 0.699 and 0.699 for abatacept, 0.450 and 0.315<br />

for etanercept, and 0.433 and 0.325 for tocilizumab at 12 and 24 months, respectively.<br />

The authors conclude that abatacept can be used for a period longer than etanercept or<br />

tocilizumab for elderly patients who cannot be treated with methotrexate [FRI0233].<br />

An abstract from Ifticene, et al. looked at steroid-sparing in 26 patients with RA from a<br />

hospital in Algeria, showing that stopping prednisone was possible in 50% of patients<br />

after 1 year of therapy [AB0409].<br />

Real-world administration and dose spacing in RA<br />

Uda, et al. performed a retrospective observational study to examine interval spacing<br />

in patients with previous good response at 4-week intervals. In 120 patients moved to<br />

6-week intervals, the majority maintained low disease activity. [SAT0203].<br />

Clinical remission was also reviewed in the real-world TOSPACE study by Sanmarti,<br />

et al. Of 401 patients included, 74 received subcutaneous tocilizumab monotherapy,<br />

and 327 received subcutaneous tocilizumab in combination with MTX or other<br />

csDMARDs. Sustained clinical remission rates were comparable between the monoand<br />

combination-therapy groups at 24 weeks. Of the 179 patients who achieved<br />

sustained clinical remission during the first phase, 89 were randomly assigned to receive<br />

subcutaneous tocilizumab 162 mg QW and 90 to receive subcutaneous tocilizumab 162<br />

mg Q2W; at Week 48, remission was maintained in 91.5% and 73.9%, respectively. Rates<br />

of AEs and SAEs leading to drug discontinuation were similar in treated monotherapy or<br />

combination therapy, and in patients treated with QW or Q2W dosing [SAT0183].<br />

Urata, et al. examined dose reduction and interval spacing in 55 patients with a twin<br />

target strategy (targeting both a SDAI


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Ito, et al. also analysed the effect of increased spacing time for intravenous administration<br />

of tocilizumab in 63 patients with RA. The intervals between administrations were 4–10<br />

weeks. Tender joint count, swollen joint count, ESR, CRP, MMP-3, DAS28-ESR, SDAI<br />

and CDAI were significantly improved. Additionally, tocilizumab was able to reduce use<br />

of prednisolone and MTX even after spacing. The authors note that MMP-3 might be a<br />

useful marker to decide the spacing period [SAT0214].<br />

In a retrospective study of 200 patients, Joffres, et al. evaluated switching from<br />

intravenous to subcutaneous administration of tocilizumab. At the next visit after the<br />

prescription of subcutaneous treatment, 89% had stayed on treatment. Efficacy was<br />

maintained, and there were no new cases of neutropenia [AB0406].<br />

Real-world efficacy in JIA<br />

Glazyrina, et al. presented the experience of tocilizumab in the treatment of 18 children<br />

with JIA at one hospital in Russia. During therapy, a decrease in disease activity was<br />

observed in all patients. Clinical disease remission was observed in 11 patients after<br />

6–9 months of treatment. Tocilizumab was well-tolerated, with AEs in only one patient<br />

(allergic skin reaction). Three patients were able to discontinue the drug due to longterm<br />

remission (3–4 years), although therapy was resumed after 1 year in two patients<br />

[AB0952].<br />

Oshlyanska, et al. performed a retrospective analysis to clarify the impact of tocilizumab<br />

on the course of JIA. Of 117 children with JIA, they identified 11 who had received<br />

tocilizumab. All patients received corticosteroid therapy before initiating tocilizumab, and<br />

2–4 high-dose DMARDs; two patients also received adalimumab prior to tocilizumab<br />

treatment. After 6 months, ESR and CRP normalised, although IL-6 remained high in 36%<br />

of patients [AB0964].<br />

Basic science<br />

Blas, et al. reported on a comparative study of IL-6 production and MMP-9 activity<br />

in fibroblast-like synoviocytes stimulated with synovial fluid from patients with<br />

osteoarthritis, RA or spondyloarthritis. They concluded that the synovial fluid of patients<br />

with inflammatory arthritis recreates a differential microenvironment for fibroblast-like<br />

synoviocytes that impacts on early phenotypic changes of these cells. The IL-6 provokes<br />

augmented and persistent MMP-9 activity in fibroblast-like synoviocytes stimulated with<br />

synovial fluid from RA or spondyloarthritis. The work identified tocilizumab as an inhibitor<br />

of all forms of MMP-9 [AB0051].


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

A poster from Moura, et al. assessed the effect of TNFi and tocilizumab on B-cell<br />

phenotype and gene expression in RA. They reported that the frequency of total CD19+<br />

B-cells in circulation was similar between controls and all RA groups, irrespective of<br />

treatment, but double negative IgD-CD27- memory B-cells were significantly increased<br />

in early and established RA when compared with controls. Treatment with TNFi and<br />

tocilizumab restored the frequency of IgD-CD27- B-cells to normal levels, but did not<br />

affect other B-cell subpopulations. TACI, CD95, CD5, HLA-DR and TLR9 expression<br />

on B-cells significantly increased after treatment with either TNF-inhibitors and/or<br />

tocilizumab, but no significant changes were observed in BAFF-R, BCMA, CD69, CD86,<br />

CXCR5, CD23, CD38 and IgM expression on B-cells when comparing baseline with posttreatment<br />

follow-ups [SAT0170].<br />

Li, et al. studied the influence of tocilizumab on lymphocyte subsets, immunoglobulin<br />

and biochemical indicators of sJIA. After 12 weeks, the proportions of CD4 + T, CD19 +<br />

B cells in the tocilizumab group were lower than baseline; CD8 and CD3 + T cells were<br />

increased in comparing with baseline. There was no significant change in CD16 + 56-NK<br />

cells, and immunoglobulins IgG, IgM, IgA were lower than baseline [AB0401].<br />

Sheng-Xiao, et al. discussed the influence of a combination of IL-2 and tocilizumab on<br />

T cell subgroups and its clinical efficacy and safety in 50 refractory patients with RA with<br />

low Treg cells. They concluded that this combination selectively stimulate Treg cells and<br />

induce autoimmune tolerance, helping to achieve rapid remission without over treatment<br />

[SAT0181].<br />

A poster from Chapman, et al. looked at the effects of tocilizumab on myostatin<br />

in 19 patients with RA in the 52-week ACT-NEUT study. Baseline serum myostatin<br />

concentrations were negatively correlated with baseline DAS28. Treatment with<br />

tocilizumab for 6 months resulted in a significant increase in serum myostatin.<br />

Furthermore, a significant association was seen between baseline myostatin and change<br />

in cholesterol at 3 months, when adjusting for baseline cholesterol, age, gender, BMI and<br />

change in BMI [SAT0209].<br />

Vobarilizumab<br />

Vobarilizumab is a nanobody ® consisting of an anti-IL-6 receptor domain and an antihuman<br />

serum albumin domain. It is currently in development for the treatment of RA.


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

Clinical efficacy in RA<br />

Dörner, et al. presented the results of a Phase 2b study in 251 patients with RA. Patients<br />

were randomized to receive one of three blinded doses of vobarilizumab or open-label<br />

tocilizumab. At Week 12, 73–81% of patients assigned to vobarilizumab achieved ACR20<br />

response; ACR50 and ACR70 were 37–49% and 16–24%, respectively. At the end of<br />

the 12-week treatment period, clinically meaningful improvement in HAQ-DI scores<br />

and remission based on DAS28CRP and DAS28ESR was observed in a substantial<br />

number of patients treated with vobarilizumab. Similar efficacy results were obtained for<br />

vobarilizumab and open-label tocilizumab [FRI0239].<br />

In an oral presentation, Dörner, et al. showcased the remission and maintenance of efficacy<br />

in 345 patients. At Week 24, up to 61% and 45% of the patients in the vobarilizumab groups<br />

achieved ACR50 or ACR70, respectively (39% and 17% on placebo). Sustained remission,<br />

defined by DAS28CRP


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

References<br />

• Aletaha D, Thorne C, Schiff M, et al. SIRUKUMAB INTEGRATED SAFETY IN RHEUMATOID ARTHRITIS PATIENTS:<br />

ANALYSIS OF THE SIRROUND PHASE 3 DATA. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract<br />

SAT0194.<br />

• Amano K, Chino K, Okada Y, et al. TOCILIZUMAB MONOTHERAPY FOR POLYMYALGIA RHEUMATICA ~ RESULTS<br />

OF 52-WEEK TREATMENT OF A PROSPECTIVE, SINGLE-CENTER, OPEN, SINGLE-ARM TRIAL. Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0984.<br />

• Blas R, Tamashiro H, Munarriz A, et al. INTERLEUKIN-6 BLOCKADE WITH TOCILIZUMAB DECREASES<br />

METALLOPROTEINASE-9 ACTIVITY IN SYNOVIAL FIBROBLASTS STIMULATED WITH SYNOVIAL FLUIDS OF<br />

PATIENTS WITH RHEUMATOID ARTHRITIS OR SPONDYLOARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract AB0051.<br />

• Burmester GR, Lin Y, Mangan EK, et al. EFFICACY AND SAFETY OF SARILUMAB MONOTHERAPY VERSUS<br />

ADALIMUMAB MONOTHERAPY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS IN THE PHASE 3<br />

MONARCH STUDY, INCLUDING SUBPOPULATIONS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract SAT0202.<br />

• Byrne E, Mark P, Khalid S, et al. TOCILIZUMAB FOR THE MANAGEMENT OF RHEUMATOID ARTHRITIS:<br />

DISCONTINUATION DUE TO INEFFICACY AND TOXICITY – EXPERIENCE FROM A LARGE TEACHING HOSPITAL.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0198.<br />

• Caetano J, Oliveira S, Alves JD. THE INFLUENCE OF FATIGUE IN THE DEFINITION OF REMISSION IN<br />

RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract AB0238.<br />

• Chapman MJ, Narayanan RP, Cross A, et al. OBSERVATIONAL STUDY ON THE EFFECTS OF IL-6 INHIBITOR<br />

THERAPY ON MYOSTATIN IN PATIENTS WITH RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract SAT0209.<br />

• Choy E, Caporali R, Xavier R, et al. SUBCUTANEOUS TOCILIZUMAB MONOTHERAPY OR COMBINED WITH A<br />

CSDMARD IN PATIENTS WITH RHEUMATOID ARTHRITIS: TOZURA, A POOLED ANALYSIS OF PHASE IV STUDIES<br />

IN 22 COUNTRIES. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0199.<br />

• Damask A, Boyapati A, Hamilton JD, et al. UGT1A1 GENETIC VARIANTS ARE ASSOCIATED WITH INCREASES IN<br />

BILIRUBIN LEVELS IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH SARILUMAB. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0228.<br />

• Dasgupta B, Campbell K, Bay-Jensen A-C, et al. THE EFFECT OF SIRUKUMAB PLUS METHOTREXATE ON<br />

CIRCULATING BIOMARKERS OF JOINT DESTRUCTION IN MODERATE TO SEVERE RHEUMATOID ARTHRITIS<br />

PATIENTS FROM THE SIRROUND-D PHASE 3 STUDY. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract OP0103.<br />

• De Benedetti F, Ruperto N, Lovell D, et al. IDENTIFICATION OF OPTIMAL SUBCUTANEOUS (SC) DOSES OF<br />

TOCILIZUMAB IN CHILDREN WITH POLYARTICULAR-COURSE JUVENILE IDIOPATHIC ARTHRITIS (PCJIA).<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract THU0503.<br />

• Domínguez-Casas LC, Loricera J, Hernández JL, et al. EFFICACY OF TOCILIZUMAB IN 31 PATIENTS WITH GIANT<br />

CELL ARTERITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0336.<br />

• Dörner T, Weinblatt M, Durez P, et al. REMISSION AND MAINTENANCE OF EFFICACY IN A PHASE 2B STUDY<br />

OF VOBARILIZUMAB, AN ANTI-INTERLEUKIN 6 RECEPTOR NANOBODY, IN PATIENTS WITH MODERATE-TO-<br />

SEVERE RHEUMATOID ARTHRITIS DESPITE TREATMENT WITH METHOTREXATE. Presented at: <strong>EULAR</strong>; 14–17<br />

June <strong>2017</strong>, Madrid, Spain. Abstract OP0098.<br />

• Dörner T, Weinblatt M, Van Beneden K, et al. RESULTS OF A PHASE 2B STUDY OF VOBARILIZUMAB, AN ANTI-<br />

INTERLEUKIN-6 RECEPTOR NANOBODY, AS MONOTHERAPY IN PATIENTS WITH MODERATE TO SEVERE<br />

RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0239.<br />

• Erlandsson E, Nadali M, Töyrä Silfverswärd S, et al. SIGNALLING THROUGH INSULIN-LIKE GROWTH FACTOR<br />

1 RECEPTOR CONTRIBUTES TO IL-6 PRODUCTION AND SUPPORTS T CELL DEPENDENT INFLAMMATION IN<br />

RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0026.


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

• Fautrel B, Senbel E, Vittecoq O, et al. SUBCUTANEOUS TOCILIZUMAB AS MONOTHERAPY OR IN COMBINATION<br />

WITH A CSDMARD IN PATIENTS WITH RHEUMATOID ARTHRITIS : 24 WEEKS RESULTS OF THE FRENCH PHASE<br />

IIIB STUDY, “TOSCA”. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0395.<br />

• Favalli EG, Biggioggero M, Puttini PS, et al. COMPARATIVE EFFICACY AND RETENTION RATE OF TOCILIZUMAB<br />

AND TNF INHIBITORS USED IN COMBINATION WITH METHOTREXATE AS FIRST-LINE BIOLOGIC THERAPY IN<br />

RHEUMATOID ARTHRITIS: DATA FROM A MULTICENTRE OBSERVATIONAL REGISTRY. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0215.<br />

• Fernández-Díaz C, Narvaez-García J, Martín-López M, et al. INTERSTITIAL LUNG DISEASE AND RHEUMATOID<br />

ARTHRITIS. MULTICENTER STUDY WITH TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract THU0134.<br />

• Fleischmann R, Hrycaj P, van Hoogstraten H, et al. SARILUMAB DOSE REDUCTION IN AN OPEN-LABEL<br />

EXTENSION STUDY IN RA PATIENTS WITH INADEQUATE RESPONSE TO TNF INHIBITORS. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0212.<br />

• Foeldvari I, Anton J, Friswell M, et al. TOCILIZUMAB IS A PROMISING TREATMENT OPTION FOR THERAPY<br />

RESISTENT JUVENILE LOCALISED SCLERODERMA PATIENTS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid,<br />

Spain. Abstract THU0511.<br />

• Frisell T, Dehlin M, Di Giuseppe D, et al. COMPARATIVE EFFECTIVENESS OF ABATACEPT, RITUXIMAB,<br />

TOCILIZUMAB AND ANTI-TNF BIOLOGICAL DMARDS IN RA: RESULTS FROM THE NATIONWIDE SWEDISH<br />

REGISTER. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0213.<br />

• Gabay C, Msihid J, Paccard C, et al. SARILUMAB SIGNIFICANTLY SUPPRESSES CIRCULATING BIOMARKERS OF<br />

BONE RESORPTION AND CARDIOVASCULAR RISK COMPARED WITH ADALIMUMAB: BIOMARKER ANALYSIS<br />

FROM THE PHASE 3 MONARCH STUDY. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0227.<br />

• Gale S, Wang J, Nebesky JM, et al. INCIDENCE OF MELANOMA IN PATIENTS WITH RHEUMATOID ARTHRITIS<br />

TREATED WITH TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0248.<br />

• Genovese MC, van Hoogstraten H, Kampman W, et al. ASSOCIATION BETWEEN CLINICAL AND RADIOGRAPHIC<br />

RESPONSES, AND PHYSICAL FUNCTION IN A PHASE 3 STUDY OF SARILUMAB PLUS METHOTREXATE IN<br />

PATIENTS WITH ACTIVE, MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June<br />

<strong>2017</strong>, Madrid, Spain. Abstract FRI0242.<br />

• Glazyrina GA, Kolyadina NA. EXPERIENCE OF TOCILIZUMAB USE IN TREATMENT OF JUVENILE IDIOPATHIC<br />

ATRTRITIS IN CHELYABINSK REGIONAL CHILDREN HOSPITAL. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid,<br />

Spain. Abstract AB0952.<br />

• Gossec L, Strand V, Proudfoot C, et al. RHEUMATOID ARTHRITIS (RA) IMPACT FOLLOWING TREATMENT WITH<br />

SARILUMAB: PATIENT REPORTED OUTCOMES USING THE RAID SCALE FROM TWO RANDOMIZED PHASE III<br />

TRIALS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0240.<br />

• Hara Y, Ishida Y, Yamaguchi Y, et al. TOCILIZUMAB INDUCED CLINICAL REMISSION IN RHEUMATOID ARTHRITIS<br />

HAD MORE RESIDUAL DOPPLER SIGNALS IN COMPARISON WITH OTHER BIOLOGICS. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0083.<br />

• Harrold LR, Reed GW, Best J, et al. COMPARATIVE EFFECTIVENESS OF TOCILIZUMAB (TCZ) MONOTHERAPY<br />

WITH TUMOR NECROSIS FACTOR INHIBITORS (TNFI) IN COMBINATION WITH VARYING DOSES OF<br />

METHOTREXATE (MTX) IN PATIENTS WITH RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract AB0407.<br />

• Ifticene MA, Hafirassou H, Benaziez R, et al. CORTICOSTEROID-SPARING IN PATIENTS WITH RHEUMATOID<br />

ARTHRITIS ON TOCILIZUMAB: FIRST EXPERIENCE OF BAB -EL- OUED HOSPITAL. Presented at: <strong>EULAR</strong>; 14–17<br />

June <strong>2017</strong>, Madrid, Spain. Abstract AB0409.<br />

• Ito S, Kobayashi D, Takai C, et al. AN ANALYSIS OF INCREASING SPACING TIME FOR THE INTRAVENOUS<br />

ADMINISTRATION OF TOCILIZUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17<br />

June <strong>2017</strong>, Madrid, Spain. Abstract SAT0214.<br />

• Joffres L, Ricard E, Pereira Gillon C, et al. STABLE EFFICACY AND SAFETY AFTER SWITCHING FROM<br />

TOCILIZUMAB INTRAVENOUS TO SUBCUTANEOUS IN RHEUMATOID ARTHRITIS : RESULTS OF A COHORT OF<br />

200 PATIENTS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0406.


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

• Kanayama Y, Kojima T, Hirano Y, et al. EFFICACY OF TOCILIZUMAB FOR SUPPRESSING RADIOGRAPHIC<br />

PROGRESSION OF CERVICAL LESIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS COMPARISON WITH<br />

METHOTREXATE TREATMENT ; TWO YEARS OF FOLLOW-UP ~A MULTICENTER REGISTRY STUDY ~. Presented<br />

at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0254.<br />

• Kikuchi E, Aoki N, Yoshioka T, Okai T. THE RETENTION RATES OF ABATACEPT IN ELDERLY RA PATIENTS (65<br />

YEARS AND ABOVE) WHO CANNOT BE TREATED WITH METHOTREXATE: COMPARISON WITH ETANERCEPT<br />

AND TOCILIZUMAB; A SINGLE-CENTER, RETROSPECTIVE, CASE-CONTROL STUDY. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0233.<br />

• Kondo T, Okada Y, Shibata A, et al. TOCILIZUMAB MONOTHERAPY FOR ADULT ONSET STILL’S DISEASE ~<br />

RESULTS OF 52-WEEK TREATMENT OF A PROSPECTIVE, SINGLE-CENTER, SINGLE-ARM, OPEN TRIAL.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract THU0577.<br />

• Kunishita Y, Yoshimi R, Nagai H, et al. WHICH FACTORS PREDICT THE RESPONSIVENESS TO TOCILIZUMAB IN<br />

RHEUMATOID ARTHRITIS? THE DIFFERENCE BETWEEN THE USAGE AS THE FIRST BIOLOGIC AND AS THE<br />

SECOND BIOLOGIC. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0416.<br />

• Lauper K, Nordström DC, Pavelka K, et al. RETENTION OF TOCILIZUMAB AS MONOTHERAPY VERSUS TNF<br />

INHIBITORS WITH CONVENTIONAL SYNTHETIC DMARDS IN RHEUMATOID ARTHRITIS PATIENTS WITH<br />

INADEQUATE RESPONSE TO TNF INHIBITORS: A STUDY FROM THE TOCERRA COLLABORATION. Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0206.<br />

• Li H, Zeng H. THE EFFICENT REGULATION OF TOCILIZUMAB FOR THE EXPRESSION OF CD4+/CD8+ T/CD19 +<br />

B CELLS AND THE IMMUNOGLOBULIN IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0401.<br />

• Loza M, Campbell K, Sweet K, et al. SIRUKUMAB TREATMENT REDUCES LEVELS OF IRON-REGULATORY<br />

PROTEINS AND AMELIORATES INFLAMMATION-ASSOCIATED ANEMIA IN RHEUMATOID ARTHRITIS PATIENTS.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0243.<br />

• Mallalieu NL, Hsu J, Wang K, et al. EVALUATION OF A DOSING REGIMEN FOR TOCILIZUMAB IN PATIENTS<br />

YOUNGER THAN TWO YEARS OF AGE WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS. Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract OP0197.<br />

• Mohan S, Michalska M, Yourish J, et al. LONG-TERM SAFETY OF TOCILIZUMAB FROM LARGE CLINICAL TRIAL<br />

AND POSTMARKETING POPULATIONS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract OP0105.<br />

• Möller B, Scholz G, Dougados M, et al. ANEMIA IS A BETTER PREDICTOR FOR RADIOGRAPHIC DAMAGE IN<br />

RHEUMATOID ARTHRITIS THAN DAS28 WHEN DETERMINED BEFORE START OF TOCILIZUMAB-TREATMENT<br />

– A SECONDARY ANALYSIS FROM THE ACT-RAY TRIAL. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract FRI0225.<br />

• Moura RA, Quaresma C, Vieira AR, et al. B-CELL PHENOTYPE AND IGD-CD27- MEMORY B CELLS ARE<br />

AFFECTED BY TNF-INHIBITORS AND TOCILIZUMAB TREATMENT IN RHEUMATOID ARTHRITIS. Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0170.<br />

• Mueller R, Graninger W, Sidiropoulos P, et al. MEDIAN TIME TO LOW DISEASE ACTIVITY IS SHORTER IN<br />

TOCILIZUMAB COMBINATION THERAPY WITH CSDMARDS AS COMPARED TO MONOTHERAPY IN PATIENTS<br />

WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSES TO CSDMARDS AND/OR TNF<br />

INHIBITORS: SUBANALYSIS OF THE SWISS AND AUSTRIAN PATIENTS FROM THE ACT-SURE STUDY. Presented<br />

at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0247.<br />

• Nakabo S, Tsuji Y, Inagaki M, et al. CLINICAL REMISSION IN TOCILIZUMAB-USING RHEUMATOID ARTHRITIS<br />

PATIENTS CAN BE OVERESTIMATED: A CROSS SECTIONAL STUDY USING ULTRASOUND SONOGRAPHY.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0673.<br />

• Oshlyanska OA, Artsymovych AG. SOME PECULARITIES OF THE COURSE OF JUVENILE IDIOPATHIC ARTHRITIS<br />

IN PATIENTS TREATED WITH TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract<br />

AB0964.<br />

• Paccard C, Msihid J, Brisacier A, et al. SARILUMAB SUPPRESSES THROMBOSIS-RELATED GENE EXPRESSION<br />

IN CIRCULATING BLOOD CELLS IN MTX-IR AND TNF-IR PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0192.


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

• Pomponio G, Tontini C, Angeletti A, et al. EFFICACY AND SAFETY OF INTRAVENOUS AND SUBCUTANEOUS<br />

TOCILIZUMAB IN A COHORT OF PATIENTS AFFECTED BY RHEUMATOID ARTHRITIS IN REAL-LIFE. Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0400.<br />

• Ruiz-Esquide V, Bastida C, Pascal M, et al. THERAPEUTIC DRUG MONITORING ON RHEUMATOID ARTHRITIS<br />

PATIENTS WITH REDUCED DOSES OF INTRAVENOUS TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract SAT0184.<br />

• Sánchez Huerta JMN, Gálvez-Romero JL, López-Rodriguez W, López A. UTILITY OF TOCILIZUMAB IN CLINICAL<br />

MANIFESTATIONS OF EROSIVE OSTEOARTHROSIS OF HANDS; REGIONAL HOSPITAL ISSSTE PUEBLA,<br />

MÉXICO. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0524.<br />

• Sanmarti R, Martín Mola E, Fonseca JE, et al. CLINICAL REMISSION IN SUBJECTS WITH RHEUMATOID<br />

ARTHRITIS TREATED WITH SUBCUTANEOUS TOCILIZUMAB AS MONOTHERAPY OR IN COMBINATION WITH<br />

METHOTREXATE OR OTHER SYNTHETIC DMARDS: A REAL-WORLD CLINICAL TRIAL (TOSPACE). Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0183.<br />

• Saraux A, Cantagrel A, Combe B, et al. FACTORS INFLUENCING THE PRESCRIPTION OF TOCILIZUMAB ALONE<br />

OR IN COMBINATION WITH DMARDS IN RHEUMATOID ARTHRITIS PATIENTS IN A REAL LIFE SETTING. POOLED<br />

ANALYSIS OF 3 OBSERVATIONAL STUDIES. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0189.<br />

• Sheng-Xiao Z, Xiao-Wen M, Xiao-Qing L, et al. LOW DOSE INTERLEUKIN-2 COMBINED WITH TOCILIZUMAB<br />

SELECTIVELY INCREASES REGULATORY T CELLS HELPING REFRACTORY RHEUMATOID ARTHRITIS PATIENTS<br />

ACHIEVE REMISSION MORE RAPIDLY. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0181.<br />

• Specker C, Kellner H, Kästner P, et al. RA PATIENTS WITH INFLAMMATORY ANEMIA BENEFIT FROM INCREASED<br />

HEMOGLOBIN AND DECREASED FATIGUE UNDER TOCILIZUMAB THERAPY. Presented at: <strong>EULAR</strong>; 14–17 June<br />

<strong>2017</strong>, Madrid, Spain. Abstract SAT0193.<br />

• Specker C, Kellner H, Kästner P, et al. TOCILIZUMAB I.V. EFFECTIVENESS IN RA PATIENTS IS INDEPENDENT OF<br />

SMOKING STATUS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract AB0396.<br />

• Strand V, Ganguly R, Li N, McQuarrie K. SIRUKUMAB LEADS TO SIGNIFICANT AND CLINICALLY MEANINGFUL<br />

IMPROVEMENTS IN HEALTH-RELATED QUALITY OF LIFE THAT MEET OR EXCEED NORMATIVE VALUES IN<br />

PATIENTS WITH RHEUMATOID ARTHRITIS REFRACTORY TO TNF INHIBITORS IN POST HOC ANALYSES OF A<br />

PHASE 3 TRIAL. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0182.<br />

• Strand V, Gossec L, Proudfoot C, et al. PATIENT REPORTED BENEFITS OF SARILUMAB MONOTHERAPY VERSUS<br />

ADALIMUMAB MONOTHERAPY IN ADULT PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS. Presented at:<br />

<strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract OP0102.<br />

• Strand V, Lampl K, Birchwood C, et al. PATIENT-REPORTED OUTCOMES IN PATIENTS WITH RHEUMATOID<br />

ARTHRITIS TREATED WITH SUBCUTANEOUS TOCILIZUMAB COMPARED WITH PLACEBO OR INTRAVENOUS<br />

TOCILIZUMAB IN COMBINATION WITH CSDMARDS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract FRI0253.<br />

• Strand V, McQuarrie K, Li N, et al. IMPROVEMENTS IN HEALTH-RELATED QUALITY OF LIFE WITH SIRUKUMAB<br />

ARE STATISTICALLY SIGNIFICANT, CLINICALLY MEANINGFUL, AND MEET OR EXCEED NORMATIVE VALUES IN<br />

RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO DISEASE-MODIFYING ANTIRHEUMATIC<br />

DRUGS: POST HOC ANALYSES OF A PHASE 3 TRIAL. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract FRI0246.<br />

• Sun Y, Hsu B, Wang D, et al. IMPROVEMENT IN MEASURES OF DEPRESSED MOOD AND ANHEDONIA IN TWO<br />

RANDOMIZED, PLACEBO-CONTROLLED PHASE III STUDIES OF SIRUKUMAB, A HUMAN ANTI-INTERLEUKIN-6<br />

ANTIBODY, IN PATIENTS WITH RHEUMATOID ARTHRITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain.<br />

Abstract THU0130.<br />

• Takeuchi T, Tanaka Y, Schiff M, et al. SUMMARY OF NEUTROPENIA IN PATIENTS WITH RHEUMATOID ARTHRITIS<br />

TREATED WITH SIRUKUMAB IN THE SIRROUND PHASE 3 CLINICAL TRIALS. Presented at: <strong>EULAR</strong>; 14–17 June<br />

<strong>2017</strong>, Madrid, Spain. Abstract FRI0252.<br />

• Talotta R, Batticciotto A, Ditto MC, et al. INDUCTION AND PROGRESSION OF SUBCUTANEOUS NODULOSIS<br />

IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOCILIZUMAB. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract AB0413.


<strong>EULAR</strong> <strong>2017</strong> Conference Highlights<br />

Interleukin 6 Science<br />

• Tanaka Y, Aletaha D, Agarwal P, et al. LONG-TERM EFFICACY AND SAFETY OF SIRUKUMAB IN PATIENTS WITH<br />

ACTIVE RHEUMATOID ARTHRITIS DESPITE ANTI-TUMOR NECROSIS FACTOR THERAPY: RESULTS OF THE<br />

RANDOMIZED, PHASE 3 SIRROUND-T STUDY. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract<br />

FRI0214.<br />

• Tanaka Y, Aletaha D, Peterson S, et al. SIRUKUMAB, AN ANTI-IL-6 CYTOKINE MONOCLONAL ANTIBODY, LEADS<br />

TO IMPROVEMENTS IN WORK PRODUCTIVITY AND GENERAL HEALTH STATUS IN PATIENTS WITH ACTIVE<br />

RHEUMATOID ARTHRITIS REFRACTORY TO ANTI-TNF THERAPY: RESULTS FROM THE PHASE 3 SIRROUND-T<br />

STUDY. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0251.<br />

• Teitsma XM, Jacobs JWJ, Welsing PMJ, et al. EFFECT OF TOCILIZUMAB IN DMARD-NAÏVE EARLY RHEUMATOID<br />

ARTHRITIS PATIENTS ON HEALTH-RELATED QUALITY OF LIFE: RESULTS OF THE U-ACT-EARLY TRIAL.<br />

Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0218.<br />

• Uda H, Shigematsu K, Saiki O. SIGNIFICANCE OF EXTENSION OF TOCILIZUMAB INFUSION INTERVALS FROM 4<br />

WEEKS TO 6 WEEKS IN RA PATIENTS WHO HAD SHOWN GOOD RESPONSE TO 4 WEEK INTERVALS. Presented<br />

at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract SAT0203.<br />

• Ueno A, Yamamura Y, Fujita K, et al. THE EFFICACY AND SAFETY OF TOCILIZUMAB THERAPY IN PATIENTS<br />

WITH POLYMYALGIA RHEUMATICA WHO WERE RESISTANT OR INTOLERANT TO GLUCOCORTICOIDS AND<br />

ADDITIONAL METHOTREXATE. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract FRI0313.<br />

• Urata Y, Satoko A, Devers B, et al. TOCILIZUMAB: DOSE REDUCTION OR INTERVAL SPACING – WHICH PROVES<br />

A BETTER TAPERING STRATEGY FOR RHEUMATOID ARTHRITIS IN CLINICAL REMISSION? Presented at: <strong>EULAR</strong>;<br />

14–17 June <strong>2017</strong>, Madrid, Spain. Abstract OP0104.<br />

• Vegas-Revenga N, Calvo-Río V, Palmou-Fontana N, et al. RAPID IMPROVEMENT WITH TOCILIZUMAB IN<br />

REFRACTORY AND SEVERE UVEITIC CYSTOID MACULAR EDEMA. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract THU0567.<br />

• Vegas-Revenga N, Calvo-Río V, Santos-Gómez M, et al. SHORT AND LONG-TERM FOLLOW-UP OF TOCILIZUMAB<br />

FOR SEVERE JUVENILE IDIOPATHIC ARTHRITIS-ASSOCIATED UVEITIS. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>,<br />

Madrid, Spain. Abstract THU0526.<br />

• Yoshimoto K, Suzuki K, Sugahara K, Tsutomu Takeuchi. LOW MOLECULAR WEIGHT BAFF SIGNALING<br />

INHIBITORS AMELIORATE IL-6, IL-10 AND IGG PRODUCTION IN VITRO AND IN VIVO MODELS OF AUTOIMMUNE<br />

DISEASES. Presented at: <strong>EULAR</strong>; 14–17 June <strong>2017</strong>, Madrid, Spain. Abstract THU0055.


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