Search

Objectives This study aimed to evaluate the relative efficacy and safety of biologic agents in patients with rheumatoid arthritis (RA) who show inadequate response to tumor necrosis factor (TNF) inhibitors. Materials and methods A meta-analysis with the Bayesian network, combining direct and indirect randomized controlled trial (RCT) data, was conducted to examine the efficacy and safety of abatacept, rituximab, tocilizumab, sarilumab, sirukumab, and secukinumab in patients with RA who showed inadequate response to TNF inhibitors. Results 8 RCTs enrolling a total of 3,617 patients fulfilled the inclusion criteria. More significant American College of Rheumatology 20% (ACR20), ACR50, and ACR70 responses were obtained using therapies similar to these biologics than with placebo. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab was probably the best treatment for ACR20 response, followed by rituximab, abatacept, sarilumab, sirukumab, secukinumab 150 mg, secukinumab 75 mg, and placebo. Furthermore, identical distribution trends were observed for ACR50 response rates. In comparison, ACR70-based SUCRA rating revealed that rituximab, followed by tocilizumab, abatacept, sirukumab, secukinumab 150 mg, sarilumab, secukinumab 75 mg, and placebo might potentially result in ACR70. There was no significant difference between the number of adverse events and severe adverse events between the treatments. Conclusion All biologic agents studied were effective in treating patients with TNF inhibitor-refractory RA; however, tocilizumab, rituximab, and abatacept appeared to be more efficient than sarilumab, sirukumab, and secukinumab. There were no differences between the treatments with respect to safety.

Objective The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab as monotherapy were assessed and compared with those of adalimumab in patients with rheumatoid arthritis (RA) who were intolerant to or responded inadequately to methotrexate (MTX). Materials and methods We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab, and adalimumab in RA patients who are intolerant to or show an inadequate response to MTX. Results Three RCTs comprising 1,066 patients met the inclusion criteria. Tocilizumab 8 mg monotherapy was associated with the most favorable surface under the cumulative ranking curve (SUCRA) for the ACR20 response rate. Compared with adalimumab, tocilizumab, and sarilumab as monotherapy showed significantly higher ACR20 response rates. Ranking probability based on SUCRA indicated that tocilizumab 8 mg had the highest probability of being the best choice for achieving ACR20 response rate, followed by sarilumab 200 mg, adalimumab 40 mg, and sirukumab 50 mg. Moreover, the ACR50 response rate showed a similar distribution pattern to that of ACR20. Regarding adverse events, the ranking probability based on SUCRA indicated that sarilumab 200 mg was possibly the safest, followed by adalimumab 40 mg, tocilizumab 8 mg, and sirukumab 50 mg. However, the number of patients who experienced serious adverse events did not differ significantly between these biologics. Conclusion Based on ACR20 and ACR50 response rates, monotherapy with tocilizumab 8 mg, followed by sarilumab and sirukumab monotherapy, was optimal for patients with RA responding inadequately to MTX or showing intolerance.

What is known and objective Both biologic and Janus kinase (JAK) inhibitor therapies have demonstrated substantial effectiveness in placebo-controlled studies in patients with active rheumatoid arthritis (RA) showing inadequate responses to tumour necrosis factor (TNF) inhibitors. The purpose of this study was to determine the relative effectiveness and safety of non-TNF biologics and JAK inhibitors in patients with RA showing insufficient response to TNF inhibitors. Methods A Bayesian network meta-analysis incorporating direct and indirect data from randomized controlled trials (RCTs) was used to investigate the effectiveness and safety of non-TNF biologics (abatacept, rituximab, tocilizumab, salirumab and sirukumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) in patients with RA showing insufficient response to TNF inhibitors. Results Nine RCTs, evaluating 3577 patients for 12 weeks fulfilled the inclusion requirements. JAK inhibitors and non-TNF biologics achieved a significant American College of Rheumatology 20% (ACR20) response relative to the placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) showed that JAK inhibitor treatment was most likely to achieve the highest ACR20 response rate, followed by non-TNF biologics and placebo. The ACR50 rate displayed similar patterns as the ACR20 response rate, but non-TNF biologics have a higher value than JAK inhibitors based on the ACR70 response rate. Adverse events did not reach statistical significance nor did serious adverse events when looking at safety over 12 weeks. The confidence intervals overlap, and there is no clinical significance to these safety data, even compared with placebo. What is new and conclusion Both non-TNF biologics and JAK inhibitors have similar effects in patients with active RA that are refractory to anti-TNF treatment, and there were no differences with regard to safety among the treatments.

Evidence suggests that effects of interleukin-6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable noncirculating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC-specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single-dose (NCT02097524 and NCT02404558) and one multiple-dose (NCT01768572) trials. The model incorporated a tolerance compartment to account for ANC nadir and beginning of recovery before maximal drug concentration after subcutaneous dosing, and absence of a nadir plateau when the ANC response is saturated after subcutaneous or intravenous dosing. The model effectively describes the ANC changes and supports neutrophil margination and tolerance as an explanation for the absence of increased infection risk associated with low ANC due to interleukin-6 pathway inhibitor treatment.

Objective: To compare efficacy and safety indicators of disease-modifying antirheumatic drugs, Sarilumab, Sirukumab, Baricitinib, Tocilizumab and Adalimumab in rheumatoid arthritis treatment by a network meta-analysis. Methods: Medline, Embase, Web of Science, The Food and Drug Administration web site, and Cochrane library were searched from build to June 1, 2020. Clinical randomized controlled trails of these 5 drugs for rheumatoid arthritis were collected for network meta-analysis. Results: A total of 4 randomized controlled trails with 2070 patients were obtained. The results of the network meta-analysis showed that: (1) There was no significant difference between the 4 drugs (Sarilumab, Sirukumab, Adalimumab, and Tocilizumab) (P > .05) in terms of American College of Rheumatology 20. (2) There was no significant difference between the 5 drugs in the aspect of the America College of Rheumatology 50% and 70% (American College of Rheumatology 50, American College of Rheumatology 70) (P > .05). (3) There was no significant difference between the 3 drugs (Sarilumab, Sirukumab, Adalimumab) in terms of reducing disease activity score 28-erythrocyte sedimentation rate in patients (P > .05). (4) No significant difference was observed among the 5 drugs in terms of incidence of adverse reactions, serious adverse reactions and withdrawal adverse reactions (P > .05). The results of the ranked probability plot indicated that Tocilizumab and Sarilumab outperform other drugs in terms of efficacy and safety. Conclusion: The results of the ranking of the 5 drugs showed that Tocilizumab and Sarilumab had the best efficacy and safety.

Background Uveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis. Main body Pan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor. Conclusion Studies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.

Compounds that target interleukin (IL)−6 pathways include antibodies against the IL-6 receptor or ligand, and inhibitors of IL-6 signal transduction. The anti-IL-6 receptor (IL-6R) monoclonal antibody tocilizumab has been licensed for several years; data from multiple studies demonstrate its efficacy and tolerability in rheumatoid arthritis as monotherapy or in combination with methotrexate. In addition, another anti-IL-6R monoclonal antibody, sarilumab, has recently been approved in both the US and EU. Anti-IL-6 monoclonal antibodies include olokizumab and clazakizumab, which both have data from phase II studies, as well as sirukumab which has completed phase III trials but may not be brought to the market. Comparative data for olokizumab versus tocilizumab intervention in rheumatoid arthritis suggest no difference in efficacy between blocking the receptor or the ligand. Head-to-head studies are needed to determine whether inhibition of the Janus kinase pathway is similar in its overall efficacy to direct inhibition of IL-6 or its receptor. The IL-6 inhibitors appear to be more effective when combined with methotrexate. However, they have shown superiority to tumour necrosis factor inhibitors when used as monotherapy, and may have an advantage in patients who cannot use methotrexate or any other conventional synthetic disease modifying anti-rheumatic drug. Regarding disease activity assessment, CDAI is a more appropriate measure than DAS28 when looking at the effect of IL-6 inhibition, as these agents interfere with the acute phase response, which is heavily weighted in the formula of DAS28.

Objective To analyze the safety and efficacy of certain biologics DMARDs (Adalimumab, Baricitinib, Pefacitinib and Sirukumab) either used alone or as a combination with MTX for management of rheumatoid arthritis. Method We conducted a systematic literature review on various phase 3 Randomized controlled trails, double blind, placebo controlled, parallel group clinical trials for 52 weeks from 2017 to 2019 conforming to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. The primary efficacy endpoints were American College of Rheumatology 20 response rate improvement criteria, other secondary endpoints were American College of Rheumatology 50/70 response rates, Health Assessment Questionnaire Disability Index, Disease Activity Score-28 for rheumatoid arthritis with Erythrocyte Sedimentation Rate/C Reactive Protein and Radiographic outcomes. Results Finally, four studies were included for qualitative synthesis in which we observed improvement in ACR 20 response rate was found in the newer agents study group. SB5 (72.4%) at week 24, Baricitinib (70%) at week 12, Pefacitinib 100 mg and 150 mg (57.7% & 74.5%) at week 12 and Sirukumab 50 mg and 100 mg (55% & 54%) at week 16 respectively. ACR 50 and ACR 70 response rate at different point in time was also found to be higher in the study group which indicates their efficacy. Conclusion In this systematic review, we observed an improvement in ACR 20 response rate and other secondary efficacy outcomes with an acceptable safety margin. From the evidence of RCTs, we have identified that newer therapeutic agents has beneficial effects when compared to existing therapy.

Introduction To evaluate the efficacy and safety of sirukumab in giant cell arteritis (GCA). Methods In this multicentre, randomised, double-blind, placebo-controlled, two-part phase 3 trial (NCT02531633; Part A [52-week double-blind treatment]; Part B [104-week follow-up]), patients with GCA were randomised (3:3:2:2:2) to sirukumab 100 mg every 2 weeks plus 6-month or 3-month prednisone taper, sirukumab 50 mg every 4 weeks plus 6-month prednisone taper, or placebo every 2 weeks plus 6-month or 12-month prednisone taper. The primary endpoint was the proportion of patients in sustained remission at week 52. Secondary endpoints included disease flare and safety. The study was terminated early (October 2017; sponsor decision). Results Of 161 patients randomised (sirukumab: n = 107; placebo: n = 54), 28 (17.4%) completed week 52 (median treatment duration: 24–30 weeks). In a revised intent-to-treat (ITT) subgroup (completed week 52 or discontinued before study termination [n = 55]); six patients (all receiving sirukumab) achieved the primary endpoint. In the ITT population (n = 161), the proportion of patients with flares (week 2–52) was lower with sirukumab (18.4–30.8%) than placebo (37.0–40.0%). The proportion of patients with flares (week 2–12) was highest with sirukumab 100 mg every 2 weeks plus 3-month prednisone taper (23.1%). In Part A, 94.4% of patients reported ≥ 1 treatment-emergent adverse event (TEAE); 19.3% reported serious TEAEs. The proportions of patients with TEAEs were generally similar across treatment arms. No deaths occurred. Conclusions Although data were limited due to early termination and shortened treatment duration, sirukumab treatment resulted in numerically lower proportions of patients with flare by week 52 versus placebo, with no unexpected safety findings. Trial Registration Clinicaltrials.gov: NCT02531633. Electronic supplementary material The online version of this article (10.1007/s40744-020-00227-2) contains supplementary material, which is available to authorized users.

Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE®, Embase®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010–2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA. Funding: Pfizer. Plain Language Summary: Plain language summary available on the journal website. Electronic supplementary material The online version of this article (10.1007/s12325-018-0757-2) contains supplementary material, which is available to authorized users.

INTRODUCTION Interleukin-6 (IL-6) is well-known for its pro-inflammatory properties, has been proven to target a wide range of cells in the joint, and has been implicated in extra-articular and articular manifestations in rheumatoid arthritis (RA). Tocilizumab (TCZ) is now widely used in patients with active RA and a number of additional agents that target the IL-6 pathways are under development, including sirukumab (SRK). Areas covered: SRK is an IgG1κ human anti-IL-6 monoclonal antibody which binds to IL-6 and prevents IL-6-mediated downstream effects. Initial trial results in phase-III studies in patients with RA seemed promising, showing improved results in patients with moderate-to-severe RA. Data derive from the phase-II study and the various SIRROUND studies (phase III). Expert commentary: The available data show that SRK50 mg every 4 weeks or 100 mg every 2 weeks will be effective in treating the RA population, with clinical improvements as early as week 2 and sustained over time. The adverse-event profile seems to be similar to TCZ, except for an increased mortality post open-label studies due to infections and cardiovascular events, our knowledge of which will be deepened with post-marketing surveillance and registry data.

Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose-response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes

The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab were assessed in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab in RA patients and an inadequate MTX or TNF inhibitor response. Fourteen RCTs, comprising 9753 patients, met the inclusion criteria. Tocilizumab 8 mg combined with MTX or as monotherapy was the most effective treatment for active RA with an inadequate MTX or TNF antagonist response, followed by sarilumab and sirukumab, regardless of MTX combination. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg + MTX had the highest probability of being the best treatment to achieve the ACR50 response rate, followed by tocilizumab 8 mg, sarilumab 200 mg, sarilumab 200 mg + MTX, sirukumab 100 mg, tocilizumab 4 mg + MTX, sirukumab 100 mg + MTX, sirukumab 50 mg + MTX, sarilumab 150 mg + MTX, adalimumab 40 mg, and sirukumab 50 mg, and placebo + MTX. No significant differences were observed in withdrawals owing to adverse events after treatment with tocilizumab 8 mg + MTX, sirukumab 100 mg + MTX, or sarilumab 200 mg + MTX. In RA patients with an inadequate MTX or anti-TNF therapy response, tocilizumab 8 mg as monotherapy and combined with MTX showed acceptable tolerability and the highest performance based on the ACR50 response rate, followed by sarilumab and sirukumab.

Clinical trials in rheumatoid arthritis (RA) involve assessment of response by endpoints including composite measures of disease activity. However, many of the components are subjective and insensitive to change and their use in phase III studies necessitates large and costly trials. In single-centre, or two-centre RA studies, Greyscale ultrasound (GSUS) and power Doppler ultrasound (PDUS) imaging of a limited joint set is an early and reliable indicator of therapeutic response.1–3 However, use of ultrasound (US) endpoints in multicentre clinical trials presents challenges of operator-dependency and variability in image acquisition, even when using the same model and settings of US machine. We undertook an exploratory multicentre, US substudy, nested within the SIRROUND-H trial,4 to evaluate effects of sirukumab and adalimumab on synovial thickness and vascularity by GSUS and PDUS, respectively, in 41 consenting subjects (online supplementary Table S1) at nine clinical sites. At each site, ultrasonographers blinded to treatment assessed 12 joints (10 metacarpophalangeal (MCP) joints plus wrists) at Weeks 0, 2, 4, 8 and 24. The same model LOGIQ S8 RD US …

Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo-controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements.

ObjectivesInterleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifierNCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs.MethodsPatients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported.ResultsOf 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both pConclusionsSirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile.Trial registration numberNCT01604343; Results.

Sirukumab, a human monoclonal antibody that selectively binds to the interleukin-6 cytokine with high affinity, is under development for the treatment of rheumatoid arthritis and other diseases. We aimed to assess the efficacy and safety of sirukumab for rheumatoid arthritis in a phase 3 study (SIRROUND-T).We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre study at 183 hospitals and private rheumatology clinics in 20 countries (Argentina, Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Taiwan, UK, and USA). Eligible participants were patients with active rheumatoid arthritis aged at least 18 years, with four or more of 68 tender joints and four or more of 66 swollen joints, who were refractory or intolerant to previous treatment with at least one anti-TNF drug. We randomly assigned patients (1:1:1) via a central interactive voice or web response system to either placebo every 2 weeks, 50 mg sirukumab every 4 weeks, or 100 mg sirukumab every 2 weeks, all given for 52 weeks or less. We allowed participants to continue using any concomitant disease-modifying antirheumatic drugs (DMARDs). We based the randomisation on a computer-generated, permuted-block schedule stratified by use of methotrexate at baseline (0,0 to12·5 mg/week, or ≥12·5 mg/week). Masking was achieved with the use of multipart labels on the study drug containers which contained directions for use and other information, but not the drug's identity. Treatments were administered by subcutaneous injection; patients assigned to 50 mg sirukumab given every 4 weeks also received a placebo injection every 2 weeks to maintain masking. At week 18, placebo-treated patients meeting early escape criteria (20% improvement in swollen and tender joint counts) were randomly reassigned to either 50 mg or 100 mg of sirukumab. All remaining placebo-treated patients were subsequently randomly reassigned at week 24 to either sirukumab dose (crossover). The primary outcome was the proportion of patients who achieved a response of at least 20% improvement at week 16 according to American College of Rheumatology criteria (ACR20) in the intention-to-treat population (all randomly assigned participants). Safety analyses included all participants who received at least one dose (partial or complete) of study drug. This study is registered at EudraCT (number: 2010-022243-38) and ClinicalTrials.gov (number: NCT01606761).Between July 25, 2012, and Jan 12, 2016, we randomly assigned 878 patients to treatment: 294 to placebo, 292 to 50 mg sirukumab every 4 weeks, and 292 to 100 mg sirukumab every 2 weeks. 523 (60%) of 878 patients had previously received two or more biological treatments including non-TNF drugs, and 166 (19%) of 878 were not taking a DMARD at baseline. The proportions of patients who achieved an ACR20 response at week 16 were 117 (40%) of 292 with 50 mg sirukumab every 4 weeks, and 132 (45%) of 292 with 100 mg sirukumab every 2 weeks versus 71 (24%) of 294 with placebo; differences compared with placebo were 0·16 (95% CI 0·09-0·23) for 50 mg sirukumab every 4 weeks and 0·21 (0·14-0·29) for 100 mg sirukumab every 2 weeks (both p0·0001). Adverse event incidences in the 24-week placebo-controlled period were similar across groups (at least one event occurred for 182 patients assigned to placebo [62%, including early escape patients switched to sirukumab at week 18] of 294; 194 [66%] of 292 with 50 mg sirukumab every 4 weeks; and 207 [71%] of 292 with 100 mg sirukumab every 2 weeks). The most common adverse events in this period were injection-site erythema (four [1%] with placebo, 22 [8%] with 50 mg sirukumab every 4 weeks, and 41 [14%] with 100 mg sirukumab every 2 weeks). At week 52, of all patients receiving sirukumab including those reassigned from placebo, the most common adverse events were again injection-site erythema (33 [8%] of 416 with 50 mg sirukumab every 4 weeks and 66 [16%] of 418 with 100 mg sirukumab every 2 weeks).In patients with active rheumatoid arthritis who were refractory or intolerant to anti-TNF drugs and other biological treatments, both dosing regimens of sirukumab were well tolerated and significantly improved signs and symptoms of the disease, compared with placebo, in this difficult-to-treat population.Janssen ResearchDevelopment, LLC, and GlaxoSmithKline.

This phase 1, randomized, open-label study assessed the absolute bioavailability and pharmacokinetic comparability of sirukumab, a human anti-interleukin-6 monoclonal antibody, following subcutaneous (SC) administration via Prefilled Syringe-UltraSafe Passive® Delivery System (PFS-U) or Prefilled Syringe-SmartJect® Autoinjector (PFS-AI; Janssen Research & Development, LLC, Spring House, Pennsylvania). A total of 144 healthy male subjects were randomized to 5 single-dose treatment groups: sirukumab 50 mg and 100 mg (each by PFS-U and PFS-AI) and sirukumab 100 mg intravenous (IV) infusion. Pharmacokinetic parameters were calculated using noncompartmental analysis. Following SC administration, maximum serum concentrations (Cmax ) and area under the concentration-vs-time curve (AUC) increased in an approximately dose-proportional manner. Median time to reach Cmax was 5 days, and mean half-life ranged from 16 to 19 days. Mean absolute bioavailability of sirukumab by PFS-AI and PFS-U, respectively, was estimated at 92.4% and 81.4% with 100 mg and 88.4% and 94.7% with 50 mg. Ratios of geometric means (90% confidence intervals) of Cmax and AUC0-77d for PFS-AI:PFS-U were 1.13 (1.03, 1.25) and 1.14 (1.05, 1.24), respectively, indicating comparable systemic exposures of sirukumab following a single 100-mg SC dose by PFS-U or PFS-AI. The incidence of antibodies to sirukumab was low (1.4%). No new safety concerns associated with sirukumab were identified at either dose.

Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6–9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US. Brodalumab, was granted a first approval in Japan in July 2016. Regulatory actions on marketing applications for brodalumab in the EU and US are not expected until 2017. In 2017, first EU or US approvals may also be granted for at least nine mAbs (ocrelizumab, avelumab, Xilonix, inotuzumab ozogamicin, dupilumab, sirukumab, sarilumab, guselkumab, romosozumab) that are not yet approved in any country. Based on announcements of company plans for regulatory submissions and the estimated completion dates for late-stage clinical studies, and assuming the study results are positive, marketing applications for at least 6 antibody therapeutics (benralizumab, tildrakizumab, emicizumab, galcanezumab, ibalizumab, PRO-140) that are now being evaluated in late-stage clinical studies may be submitted during December 2016* or 2017. Other ‘antibodies to watch' in 2017 include 20 mAbs are undergoing evaluation in pivotal studies that have estimated primary completion dates in late 2016 or during 2017. Of these, 5 mAbs are for cancer (durvalumab, JNJ-56022473, ublituximab, anetumab ravtansine, glembatumumab vedotin) and 15 mAbs are for non-cancer indications (caplacizumab, lanadelumab, roledumab, tralokinumab, risankizumab, SA237, emapalumab, suptavumab, erenumab, eptinezumab, fremanezumab, fasinumab, tanezumab, lampalizumab, brolucizumab). Positive results from these studies may enable submission of marketing applications in 2017 or 2018, or provide justification for additional studies. *See note added in proof for update through December 31, 2016.

Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab's effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.

Introduction Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction. Methods Nineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis. Results Compared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C max) and area under the concentration–time curve extrapolated to infinity (AUC∞) were 54.1 % (42.2–69.4 %) and 54.7 % (47.2–63.3 %), respectively. No changes occurred in time to C max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration. Conclusions Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam. Clinical trial registration number NCT02017639. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0462-8) contains supplementary material, which is available to authorized users.

Interleukin-6 (IL-6) signaling is a critical target in inflammatory pathways. Today, tocilizumab (TCZ) and sarilumab (SAR), two IL-6 receptor-inhibiting monoclonal antibodies, are widely used in the treatment of rheumatoid arthritis (RA), with a favorable efficacy/safety profile. Successful introduction of such agents in the treatment of RA has encouraged the development of other agents targeting different points of the pathway. Sirukumab (SRK), a human anti-IL-6 monoclonal antibody, has been evaluated in clinical trials and showed largely similar clinical efficacy compared with TCZ and other IL-6 pathway-targeting agents. Furthermore, the drug safety profile seemed to reflect the profile of adverse effects and laboratory abnormalities seen in other inhibitors of the IL-6 pathway. However, increased death rates under SRK treatment compared with placebo raised safety concerns, which led to the decision by the FDA to decline the approval of SRK in August 2017. However, during the 18-week true placebo-controlled period, mortality rates were identical in the placebo- and SRK-treated patients. Comparisons after week 18 may be confounded by some factors, and also the ‘crossover’ design resulted in various treatment groups with varying drug exposure periods. The limited placebo exposure relative to SRK exposure makes interpretation of mortality rates difficult. We do not know whether the imbalance in mortality rates seen for SRK is a true safety signal or a result of bias due to the study design. Therefore, further long-term clinical data as well as basic research is needed to allow deeper insight into IL-6 signaling.

ObjectiveInterleukin (IL)-6 is a pleiotropic cytokine involved in the pathophysiology of rheumatoid arthritis (RA). Sirukumab is a human monoclonal antibody that binds to IL-6 with high affinity and specificity.MethodsThis long-term extension (LTE) study of the SIRROUND-D and SIRROUND-T studies assessed long-term safety and efficacy of sirukumab in adults with moderate-to-severe RA refractory to conventional disease-modifying antirheumatic drug therapy or antitumor necrosis factor agents. Patients received sirukumab 100 mg subcutaneously (SC) every 2 weeks (q2w) or sirukumab 50 mg SC every 4 weeks (q4w).Results1820 patients enrolled in the LTE; median exposure was 2.34 and 2.07 years in sirukumab 50 mg q4w and 100 mg q2w groups, respectively. Adverse events (AEs) occurred in similar proportions between groups, with the exception of major adverse cardiovascular events (MACE), which were more common in the 50 mg q4w versus 100 mg q2w group (2.2% vs 1.0%), and injection-site reactions, more common in the 100 mg q2w group versus 50 mg q4w group (7.5% vs 3.7%). The most common serious AEs were infections (10% of the patients); 32 (1.8%) patients died during the study (primarily from serious infection and MACE). Malignancies were reported in 24 (1.3%) patients. Gastrointestinal perforations, hepatobiliary abnormalities and changes in laboratory parameters were rare. Reductions in RA signs and symptoms and improvements in physical function were maintained throughout the LTE.ConclusionsThe safety profile of sirukumab in the LTE remained consistent with that reported in SIRROUND-D and SIRROUND-T and efficacy was maintained.Trial registration numberNCT01856309.

Objective To assess the efficacy and safety of sirukumab, an anti-interleukin-6 monoclonal antibody, for the treatment of patients with active lupus nephritis (LN). Methods Patients with class III or class IV LN (as determined by renal biopsy within 14 months of randomization) who had persistent proteinuria (>0.5 gm/day) despite receiving immunosuppressive therapy and who were being treated with stable doses of a renin-angiotensin system blocker were randomized (5:1) to receive treatment with sirukumab at a dose of 10 mg/kg intravenously (n = 21) or placebo (n = 4) every 4 weeks through week 24. The primary end point was the percent reduction in proteinuria (measured as the protein-to-creatinine [P:C] ratio in a 12-hour urine collection) from baseline to week 24. Results Twenty-five patients were enrolled, of whom 19 (76.0%) completed treatment through week 24 and 6 (24.0%) discontinued the study agent early, with 5 of the 6 discontinuing due to adverse events. At week 24, the median percent change in proteinuria from baseline to week 24 in sirukumab-treated patients was 0.0% (95% confidence interval -61.8, 39.6). In contrast, the 4 placebo-treated patients showed an increase in proteinuria (median percent reduction -43.3%) at week 24. Of note, a subset of 5 sirukumab-treated patients had ≥50% improvement in their P:C ratio through week 28. In the sirukumab group, 47.6% of patients experienced ≥1 serious adverse event through week 40; most were infection-related. No deaths or malignancies occurred. No serious adverse events were observed in the 4 placebo-treated patients. Conclusion This proof-of-concept study did not demonstrate the anticipated efficacy nor did it demonstrate an acceptable safety profile for sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment.

Background The interest in pharmaceutical trials in giant cell arteritis (GCA) is increasing. Trial recruitment may be more challenging in GCA than in other rheumatic diseases because of a higher proportion of elderly patients who are additionally faced with a new diagnosis when being considered for trial participation. Objectives To analyse the eligibility of newly diagnosed and flaring GCA patients in one centre for randomization in the SIRRESTA trial (ClinicalTrials.gov Identifier, NCT02531633; sirukumab versus placebo), to list reasons for non-randomization, and to compare eligible with non-eligible patients. Methods All patients with newly diagnosed or relapsing GCA considered for trial participation between August 2016 until trial termination in October 2017 were included. The trial was prematurely terminated by the sponsor based on the decision to discontinue development of sirukumab in autoimmune diseases. Analysis of variance, two-sided Fisher’s exact and Pearson’s chi-squared tests were applied for calculating statistical significance. Results Ninety-five patients were pre-screened. Fifteen of these patients were screened and only 12 of the 95 (13%) pre-screened GCA patients were eligible for randomization based on inclusion and exclusion criteria. The other 83 patients were not eligible for one or more of the following reasons: Concomitant diseases (42%) including second autoimmune disease (11%), malignancy (6%), history of diverticulitis (5%), hepatopathy (2%), renal insufficiency (1%) frailty (6%) and dementia (2%), ischaemic disease (2%; 1 myocardial infarction and 1 severe tongue necrosis), abnormal or inconclusive tests for tuberculosis (5%) and hepatitis (1%); failure to meet inclusion criteria (41%), including symptoms (12%), histology/imaging (1%), exceedance of maximum glucocorticoid dose (7%), too low ESR and CRP (10%), too long treatment duration (11%); declined consent (29%), before (11%) and after receiving the consent form (18%); too long distance to study centre (5%). Patients eligible for the trial were younger. They had no ischaemic complications (see table 1). A higher proportion of relapsing GCA patients were included. This subgroup of a larger trial represents only data from one centre. It may not be representative for the findings in other centres or the whole study. Conclusions Many newly diagnosed or relapsing GCA patients were not eligible for a trial due to concomitant diseases, failing inclusion criteria or declined consent. Eligible patients were younger; and more had relapsing disease. Disclosure of Interest W. Schmidt Grant/research support from: Roche, GSK (principle investigator), Consultant for: Roche, GSK, Sanofi, Speakers bureau: Roche, K. Hofheinz: None declared, S. Burger Grant/research support from: GSK (sub-investigator), V. Schafer Grant/research support from: GSK (sub-investigator), A. Juche Grant/research support from: GSK (sub-investigator)

Background Interleukin 6 (IL-6) inhibitors constitute a therapeutic option for patients with rheumatoid arthritis (RA). Currently, apart from Tocilizumab (TCZ), we have data from other drugs targeting the IL-6 pathway. Objectives To review published evidence on safety and efficacy of IL-6 inhibitors in RA. Methods We performed sensitive systematic literature searches in Medline and Cochrane (up to October 2017), screened EULAR and American College of Rheumatology meeting-abstracts. An expert librarian designed the strategies that included Mesh and text word terms. The search was limited to human RA, adults and the English and Spanish language. The inclusion criteria were as follow: 1) RA patients on IL-6 Inhibitors including TCZ, sarilumab (SAR), olokizumab, sirukumab and clazakizumab; 2) Placebo and an active comparator were accepted as comparators; 3) Articles including typical efficacy and safety variables such as DAS-28, radiographic progression or the infections rate; 4) Only meta-analyses, systematic reviews and clinical trials were selected. Two reviewers screened the titles and abstracts of the retrieved articles independently. They also collected the data from the studies included by using ad hoc standard forms. All collection was double by article and independent. Subsequently, a secondary manual search of the bibliography of the articles that were finally included was performed. Evidence tables were produced. The quality was evaluated with the Oxford 2009 scale. Results We included 64 articles of moderate-high quality, variable duration, between 12 and 108 weeks. These articles analysed more than 8000 patients with RA, most of them with established RA (although there are data on early RA), with high disease activity and severity criteria. More than a half of the studies are of TCZ. IL-6 inhibitors were effective both in the short and long term in terms of clinical remission, RA activity, radiographic progression, function, fatigue, bone metabolism, morning stiffness, pain, quality of life, or anaemia. They also decreased and even normalised CRP values in a rapid and sustained manner. The efficacy of blocking IL-6 has been seen in RA refractory to DMARD or anti-TNFα and in MTX-naive patients, as well as in the intravenous and subcutaneous formulations (TCZ). TCZ and SAR are more effective than adalimumab in monotherapy. In general, no statistically significant differences were found between combined therapy and monotherapy. In terms of safety, the rate of adverse events increased over time and with the concomitant use of DMARDs. Infections and hypersensitivity reactions were the most frequent adverse events and infections the most frequent serious adverse events. IL-6 inhibitors were associated with a rapid and subsequently sustainable increase in serum lipid parameters, although this was not associated with a higher prevalence of cardiovascular events and related mortality, nor was it associated with neoplasms. Transaminase elevations were generally mild and without serious disorders. The incidence of gastrointestinal perforations was very low, and it was associated with a previous history of diverticulitis. Conclusions IL-6 inhibitors are effective to control RA activity and symptoms and to prevent radiographic damage in different disease profiles, with an acceptable safety profile. Disclosure of Interest None declared

Background: A humanized, anti-human IL-6 receptor monoclonal antibody, tocilizumab, was developed to block IL-6 signaling and has been used as an effective therapeutic agent for patients that do not respond to methotrexate (MTX) or tumor necrosis factor (TNF) inhibitor. The successful use of tocilizumab in RA stimulated the development of other biologics targeted to the IL-6 pathway, such as anti-IL-6R (sarilumab) or anti-IL-6 (sirukumab) antibodies. Objectives: The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab were assessed in patients with rheumatoid arthritis (RA) and an inadequate response to MTX or TNF inhibitors. Methods: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab in RA patients and an inadequate MTX or TNF inhibitor response. Results: Fourteen RCTs, comprising 9,753 patients, met the inclusion criteria. Tocilizumab 8 mg combined with MTX or as monotherapy was the most effective treatment for active RA with an inadequate MTX or TNF antagonist response, followed by sarilumab and sirukumab, regardless of MTX combination. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg+MTX had the highest probability of being the best treatment to achieve the ACR50 response rate, followed by tocilizumab 8 mg, sarilumab 200 mg, sarilumab 200 mg+MTX, sirukumab 100 mg, tocilizumab 4 mg+MTX, sirukumab 100 mg+MTX, sirukumab 50 mg+MTX, sarilumab 150 mg+MTX, adalimumab 40 mg, and sirukumab 50 mg, and placebo+MTX. No significant differences were observed in withdrawals owing to adverse events after treatment with tocilizumab 8 mg+MTX, sirukumab 100 mg+MTX, or sarilumab 200 mg+MTX. Conclusions: In RA patients with an inadequate MTX or anti-TNF therapy response, tocilizumab 8 mg as monotherapy and combined with MTX showed acceptable tolerability and the highest performance based on the ACR50 response rate, followed by sarilumab and sirukumab. References [1]Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R, Investigators O. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. The Lancet2008;371:987–997. [2]Genovese M, Fleischmann R, Fiore S, Radin A, Fan C, Huizinga T. SAT0117 Sarilumab, a Subcutaneously-Administered, Fully-Human Monoclonal Antibody Inhibitor of The IL-6 Receptor: Relationship Between Eular Responses and Change from Baseline of Selected Clinical Parameters. Annals of the Rheumatic Diseases2013;72:A620-A620. [3]Xu Z, Bouman-Thio E, Comisar C, Frederick B, Van Hartingsveldt B, Marini JC, Davis HM, Zhou H. Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study. British journal of clinical pharmacology2011;72:270–281. Disclosure of Interest: None declared

Background The addition of biological (b) and new targeted synthetic (ts) DMARDs agents in chronic inflammatory arthritis (CIAs) therapeutic strategies has improved the possibility of controlling disease activity and slowing the progression of joint damage. However their impact on work participation is unclear. Objectives To assess the effect of biological and tsDMARDs versus conventional treatments in patients with CIAs on work outcomes : employment, presenteeism and absenteeism. Methods A systematic review of the literature using Pubmed-Medline and the Cochrane library was performed until January 2017. All randomised controlled trials (RCT) and controlled cohorts (CC) comparing work outcomes in patients with rheumatic diseases such as rheumatic arthritis (RA), ankylosing spondylarthris (AS) and psoriatic arthritis (PsA) treated with biological or tsDMARDs versus conventional therapies were selected. Statistical analysis determined in each study effect size (ES) or odds-ratios (OR) as appropriate to assess the magnitude of treatment effect. Pooled ES and OR were computed by meta-analysis. A random effect model was used in case of heterogeneity. Results Thirty six RCTs and eight CCs were analysed ie 12 769 patients with conventional treatment and 19 875 patients with bDMARD or tsDMARD (4619 Infliximab, 4629 Etanercept, 3872 Adalimumab, 670 Golimumab, 2101 Certolizumab, 691 Abatacept, 444 Sirukumab, 1668 Baricitinib, 672 Tofacitinib, 365 Sarilumab, 444 Sirukumab etc); 34 studies included 30 423 patients with RA, 7 studies included 1496 patients with AS and 3 studies included 725 patients with PsA. This meta-analysis showed in patients treated by bDMARD vs conventional treatment: - a significant decrease of accumulated missed workdays at week 24: ES −0.34 IC95%[−0.6; −0.08] and at week 52: ES −0.04 IC95% [–0.29; 0.2], - a significant decrease of patients loosing hours due to CIAs: RR 0.63 IC95%[0.48; 0.83], - a significant improvement in VAS productivity: ES −1.81 IC95%[−2.61; −1.01], - For the employment loss, the positive effect of bDMARDs was nearly significant: OR 0.60 IC95% [0.33; 1.09]. Conclusions Despite the heterogeneity of the data, this meta-analysis showed the beneficial effect of bDMARDs on both absenteeism and presenteeism in CIAs. Thus the high cost of biologic agents could be partly balanced with savings in indirect costs. Disclosure of Interest C. Traverson: None declared, A. tubery: None declared, C. Hua Consultant for: Pfizer, BMS, abbvie, F. Barchechath-Flaisler Consultant for: Roche Pharmaceuticals, C. Lukas Consultant for: Abbvie, BMS, Celgene, Janssen, MSD, Novartis, Pfizer, Sanofi, Schering, Roche- Chugai, UCB, B. Combe Grant/research support from: Pfizer, UCB, Consultant for: Abbvie, BMS, Janssen, Lilly, MSD, Novartis, Pfizer, Roche-Chugai, UCB, Speakers bureau: BMS, Janssen, Lilly, MSD, Pfizer, Roche-Chugai, UCB, J. Morel Consultant for: Abbvie, BMS, Celgene, Janssen, Medac, MSD, Novartis, Pfizer, Sanofi, Schering, Roche- Chugai, UCB, C. Gaujoux-Viala Grant/research support from: Pfizer, Consultant for: Abbvie, BMS, Celgene, Janssen, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi, Roche- Chugai, UCB

To characterize the dose-exposure-response relationship of sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of sirukumab E-R to support dose recommendations in patients with RA.

To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52.Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

Rheumatoid arthritis (RA) is an immune-mediated condition which primarily affects the joints, but with critical extra-articular manifestations, including a significantly increased cardiovascular risk. Patients suffering from RA can develop deforming and disabling alterations of the affected joints. Their quality of life can be substantially affected, and their life expectancy is shorter compared to that of healthy subjects. Fortunately, several pathogenic mechanisms characterizing RA have been identified, leading to the development of targeted drugs. Inhibitors of tumor necrosis factor (TNF) were the first developed among biological medications and they dramatically changed the therapeutic perspectives of RA patients. Now, 20 years after the licensing of etanercept (the first anti-TNF drug), more than 10 different biological agents have been approved by the U.S. Food and Drug Administration (FDA). Additionally, more and more drugs are under investigation in clinical trials. This review will focus on the more recently approved monoclonal antibodies and the more promising antibodies under investigation.