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In this cohort of patients with non-paraneoplastic autoimmune retinopathy and cystoid macular edema (CME), treatment with anti-interleukin-6 antibodies was associated with reduced CME, partial restoration of the ellipsoid zone on optical coherence tomography, and a trend towards improved visual acuity.

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a chronic autoimmune disease of the central nervous system that causes recurrent attacks of optic neuritis, myelitis, and brainstem symptoms, resulting in severe neurological disability. Preventive treatment with immunosuppressive agents reduces relapse rate and improves long-term prognosis. In recent years, the potential therapeutical effect of new agents has been investigated. Two of these, the anti-interleukin 6 (IL-6) agents tocilizumab and satralizumab, have been studied in active NMOSD. Objective: To systematically review the current data regarding the efficacy and safety of anti-IL-6 agents in NMOSD. Result: Fourteen case reports and 5 case series of intravenous tocilizumab have shown beneficial clinical and paraclinical effects compared to commonly used therapies, and another case series of subcutaneous tocilizumab has shown it is as effective as the IV formulation. A phase 2 comparative trial has shown tocilizumab IV to be more effective than azathioprine for relapse prevention. A phase 3 trial of subcutaneous satralizumab versus placebo, has shown a lower risk of relapse in the sartralizumab-treated group, both as add-on therapy to stable immunosuppressant and as monotherapy. Tocilizumab also reduced pain severity in two trials and fatigue scores in one trial, but satralizumab did not significantly improve pain and fatigue. Adverse events with both agents were relatively mild and comparable to placebo and azathioprine. Conclusions: The anti-Il-6 agents tocilizumab and satralizumab show promising results in active NMOSD. Further randomized, larger-scale trials are needed to better define the role of these agents in the growing arsenal of NMOSD treatments.

Although severe acute respiratory virus 2 (SARS-CoV-2)-infected patients tend to present with mild to moderate symptoms, some may develop severe or life-threatening disease. There remains an urgent need for efficacious management of COVID-19, because despite current ongoing clinical treatment trials, no effective treatments have been reported. Previously, our analysis demonstrated that excessive inflammatory responses, marked by an elevated level of interleukin-6 (IL-6) and C- reactive protein (CRP), are strongly associated with COVID-19 progression. Moreover, there is also a probable association between the disease progression observed in COVID-19 with IL-6 gene polymorphism. This article summarizes the cumulative evidence on the efficacy of anti-IL-6 receptor (anti-IL-6R) antibody among severe COVID-19-infected patients. Additionally, a meta-analysis was also performed to estimate the association between IL-6 gene polymorphism with predisposition as well as disease severity of pneumonia in general. Our analysis confirmed that anti-IL-6R antibody treatment could effectively treat severe COVID-19-infected patients, marked by suppression of CRP and improvement of clinical symptoms. The second analysis showed that although IL- 6 gene polymorphism did not predispose to pneumonia, carrier status of the IL-6–174C allele is associated with a higher level of IL-6 production and pneumonia severity. Altogether, our study strengthens the notion that IL-6 plays a pivotal role in COVID-19 progression, and suppression of IL-6 signalling cascade shows a promising therapy in severe forms of SARS-CoV-2 infection.

Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Background McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16–1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice. Methods Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16–1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines. Results Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16–1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16–1 treated groups. Conclusions Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes.

We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement. We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs. Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement. aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.

Background Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. Methods We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. Results Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. Conclusions Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (a-IL6R mAbs). We present data showing that direct neutralization of IL-6 with an a-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of a-IL-6R mAb when the treatment was delayed 48 hrs post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (α-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an α-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 hrs post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

• Discussion of the role of immunomodulatory agents to reduce the cytokine storm in severe cases of COVID-19. • Potential immunomodulatory agents currently used in the treatment of COVID-19 (chloroquine, hydroxychloroquine and tocilizumab) are discussed. • Other immunomodulatory agents with good safety profiles may be considered for use in combination with antiviral drugs for the treatment of severe or critical cases of COVID-19.

The main aspects of severe COVID-19 disease pathogenesis include the increasing hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of the cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed that can efficiently and swiftly block TNFα, IL-6, and the inflammatory cytokine cascade in order to curb inflammation and prevent fibrosis, and lead to disease remission.Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of our novel C. sativa lines may be used to modulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. To analyze the anti-inflammatory effects of novel C. sativa lines, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis lines.We noted that out of seven studied extracts of novel C. sativa lines, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. Most importantly, one of the tested extracts had no effects at all, and one exerted effects that may be deleterious, signifying that cannabis is not generic and cultivar selection must be based on thorough pre-clinical studies.The observed pronounced inhibition of TNFα and IL-6 is the most important finding, as these molecules are currently considered to be the main actionable targets in COVID-19 cytokine storm and ARDS pathogenesis. Many currently trialed agents, such as anti-TNFα and anti-IL-6 biologics are expensive and cause an arrays of side effects. On the other hand, anti-TNFα and anti-IL-6 cannabis extracts that are generally regarded as safe (GRAS) modalities can be a useful addition to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

Many pro-inflammatory cytokines especially tumor necrotic factor alpha (TNFα), interleukin (IL)-1β, and IL-6 have crucial role in the pathogenesis of endometriosis. In this study, we investigated the immune-modulatory role of humanized anti-IL-6 receptor monoclonal antibodies in the treatment of endometriosis. This is a prospective, randomized, controlled, blinded study in which Sprague Dawley rats were used as animal model of endometriosis. Animals were randomly divided into two groups, a test group which received tocilizumab (Actemra; Roche, Switzerland) and a control group which received saline. Afterwards, a comparison was done between the eutopic and ectopic endometrium that was excised from both groups, histopathologically and immune-histochemically. Histopathologic assessment and immune-histochemical staining were performed using antibodies against IL-6. Tocilizumab significantly suppressed the volume of endometriotic lesions compared with non-treated rats (P = 0.006) and atrophied the ectopic endometrial-like epithelium (in 42.8% of treated rats vs 0% in the control group). Tocilizumab also decreased the anti-IL-6 receptor immune-histochemical staining intensity in ectopic endometrium (from non to +++ in the test group vs ++ or more in the control group), with no apparent difference in the eutopic one reflecting the down-regulation of IL-6-producing cells in ectopic endometriotic lesions. In rats with induced endometriosis, anti-IL-6 receptor monoclonal antibodies could offer a new horizon of usage of this immune-modulatory biologic drug, used in other autoimmune diseases, in treatment of endometriosis.

Recent literature suggests that severe COVID-19 is associated with an exaggerated immune response during viral infection, resulting in cytokine storm. Although elevated plasma interleukin 6 (IL-6) has been reported in severe COVID-19 infections, and treatment with anti-IL-6 (tocilizumab) has demonstrated promising outcomes both domestically and abroad, reports remain limited and therapeutic regimens vary considerably. Furthermore, research pertaining to transplant recipients, COVID-19 infection, and anti-IL-6 therapy remains underdeveloped. Herein, we report the successful treatment of the only reported facial vascularized composite allograft (VCA) recipient who contracted severe COVID-19 and the first reported VCA recipient with COVID-19 infection that received anti-IL-6 immunotherapy resulting in an excellent recovery despite his multiple preexisting and COVID-19-related comorbidities-adult respiratory distress syndrome, acute renal failure requiring hemodialysis, and concomitant sepsis due to extensive drug-resistant bacterial pneumonia upon presentation. To date, he has not demonstrated any anti-IL-6 drug-related adverse effects. This preliminary report also suggests that our immunosuppressed VCA patients can indeed demonstrate a robust cytokine response during COVID-19 infection and may also respond favorably to emerging anticytokine immune therapies. We hope that our experience proves helpful to other centers that might encounter critically ill VCA recipients in the ongoing COVID-19 pandemic and in the years to follow.

Background: In the previous phase 1 study BCD-089 (INN: levilimab) was well-tolerated, had favorable safety profile and low immunogenicity1. Here we report 12-week efficacy and safety results of ongoing phase 2 clinical study of BCD-089 in patients with active RA. Objectives: This study is aimed to assess efficacy and safety of 2 dosing regimens of BCD-089 in patients with MTX-IR active RA. Methods: During this multicenter double-blind placebo-controlled randomized clinical study (NCT03455842) 105 MTX-IR patients with active RA (ACR2010) were assigned (1:1:1) to receive 162 mg of BCD-089 s.c. (QW arm and Q2W arm) or PBO. MTX (10-25 mg/week) was used in all groups. After completion of 12-week blinded period patients from QW/Q2W arms continued the treatment, patients from PBO arm were switched to BCD-089 Q2W until Wk56. The primary efficacy endpoint was the rate of ACR20 at Wk12. Secondary endpoints included ACR50/70 and DAS28-CRP(4). The safety was routinely evaluated. Results: The efficacy analysis showed that 95% confidence interval for BCD-089 treatment effect relative to PBO was [38.45 – 81.55] for QW arm and [16.53 – 63.4] for Q2W arm, which confirms the superiority to PBO of either dosing regimens. Summary of efficacy results is presented in table 1. The majority of adverse events (AE) were laboratory abnormalities. The spectrum of AEs is similar to other IL6R inhibitors (Table 2). Three serious AE (SAEs) were reported: community-acquired pneumonia (QW arm, treatment-related), acute cholecystitis (PBO arm, not related, did not lead to treatment discontinuation), and acute heart failure leading to death (Q2W arm, not related). One case of moderate local reaction (erythema) was reported in QW arm. Conclusion: BCD-089 in combination with MTX had superior efficacy compared with MTX plus PBO in MTX-IR patients with active RA. BCD-089 showed safety profile consistent with other IL6R inhibitors. Further clinical studies are needed. Reference: [1] Khlyabova P, et al. doi: 10.1136/annrheumdis-2018-eular.2410 Disclosure of Interests: V Mazurov Grant/research support from: JSC BIOCAD, Evgeniy Zotkin: None declared, Elena Ilivanova Grant/research support from: JSC BIOCAD, Tatyana Kropotina Grant/research support from: JSC BIOCAD, Tatyana Plaksina Grant/research support from: JSC BIOCAD, Olga Nesmeyanova Grant/research support from: JSC BIOCAD, Nikolaj Soroka: None declared, Alena Kundzer: None declared, Anton Lutskii Employee of: JSC BIOCAD, Ekaterina Dokukina Employee of: JSC BIOCAD, Ekaterina Chernyaeva Employee of: JSC BIOCAD, Roman Ivanov Employee of: JSC BIOCAD

Chronic pain is a significant symptom in patients with autoimmune encephalomyelitis, such as multiple sclerosis and neuromyelitis optica. The most commonly used animal model of these diseases is experimental autoimmune encephalomyelitis (EAE). We previously reported that evoked pain, such as mechanical allodynia, was improved by an anti-IL-6 receptor antibody in EAE mice. However, few reports have evaluated spontaneous pain in EAE mice. Here, we assessed spontaneous pain in EAE mice by utilizing the Mouse Grimace Scale (MGS, a standardized murine facial expression-based coding system) and evaluated the influence of an anti-IL-6 receptor antibody (MR16-1). EAE was induced in female C57BL/6J mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35-55 emulsified in adjuvant and administration of pertussis toxin. Mice were placed individually in cubicles and filmed for about 10 min. Ten clear head shots per mouse from the video recording were given a score of 0, 1, or 2 for each of three facial action units: orbital tightening, nose bulge, and ear position. Clinical symptoms of EAE were also scored. Measurement of 5-HT in the spinal cord and functional imaging of the periaqueductal gray (PAG) were also performed. Compared with control mice, MGS score was significantly higher in EAE mice. MR16-1 prevented this increase, especially in pre-onset EAE mice. Promotion of spinal 5-HT turnover and reduction of PAG activity were observed in pre-onset EAE mice. These results suggest that MR16-1 prevented spontaneous pain developed before EAE onset.

Background:Emerging evidence during the last two decades supports a pivotal role of Interleukin 6 (IL-6) in the pathogenesis of Systemic Sclerosis (SSc). Standard immunosuppressive agents are often inadequate to control disease activity in SSc patients and treatment failure of multiple regimens is frequent in real-world practice.Objectives:To examine the efficacy and safety of interleukin-6 receptor inhibition by tocilizumab in selected real-world patients with SSc.Methods:Twenty-one patients (20 women, 16 diffuse SSc, mean age: 52±10 years, mean disease duration: 6.4±3.7 years, all with negative rheumatoid factor and anti-cyclic citrullinated antibodies, none with overlap syndrome with RA) with active joint and skin involvement refractory to corticosteroids (n=21), methotrexate (n=17), cyclophosphamide (n=10), mycophenolate (n=7), rituximab (n=1), leflunomide (n=2), hydroxychloroquine (n=2), and hematopoietic stem cell transplantation (n=2) who received weekly tocilizumab (162 mg subcutaneously) in an academic center, were monitored prospectively. Changes in Eustar modified activity index (MAI), modified Rodnan skin score (mRSS), disease activity score (DAS)28, lung function tests (LFTs) and patient reported outcomes (PROs) were analyzed at one year of treatment and at the end of follow-up.Results:One patient discontinued tocilizumab after 3 months due to inefficacy. During the first year of treatment, 12 patients achieved low disease activity (mean MAI change -2.9±1.8, pConclusion:Tocilizumab was effective in refractory joint and skin involvement irrespective of SSc disease duration or subtype. Long-term retention rates and disease stabilization for most real-world patients suggest that tocilizumab might be a valuable choice for difficult-to-treat SSc.Table 1.Clinical and laboratory parameters and measures (mean ± SD) at baseline and after one year of treatment with tocilizumab in 20 patients with Systemic SclerosisBaseline1st yearchangepModified activity index4.9 ± 1.62.0± 1.2-2.9 ± 1.8mRSS 21.5 ± 9.5 14.6 ± 6.6-6.9 ± 5.9DAS28 5.3 ± 0.73.4 ± 0.6-1.9 ± 0.8FVC (% of predicted) 82 ± 19.5 79 ± 19.1-2.9 ± 12 0.389DLCO (% of predicted) 60.4 ± 16.361.1 ± 18.4 0.7 ± 12.3 0.844ESR (mm/1st hr)35.6 ± 17.212.9 ± 11.8 -22.8 ± 19.10.001CRP (mg/l)13.2 ± 12.51.2 ± 2.1 -12 ± 13.10.006SHAQ1.6 ± 0.81.0 ± 0.7 -0.6 ± 0.5VAS patient global score37.8 ± 16.860.5 ± 15.4 22.7 ± 20.3VAS physician global score33.4 ± 13.263.2 ± 13.9 29.8 ± 15.6mRSS: modified Rodnan skin score; DAS28: disease activity score 28; FVC: forced vital capacity; DLCO: diffusing lung capacity for carbon monoxide; ESR: erythrocyte sedimentation rate; CRP: c-reactive protein; SHAQ: scleroderma health assessment questionnaire; VAS: visual analogue scaleDisclosure of Interests:None declared

Background:Adiponectin is an adipokine with anti-inflammatory, anti-atherosclerotic and cardioprotective effects that also contributes to the pathogenesis of metabolic syndrome (MetS) [1]. MetS is frequently observed in patients with rheumatoid arthritis (RA), increasing the risk of cardiovascular (CV) morbidity and mortality in these patients [1-3]. A recent study of our group disclosed a short-term effect of anti-IL-6 therapy on serum levels of leptin (another adipokine with pro-inflammatory functions, related with MetS and CV disease) in RA patients [4]. Accordingly, it is plausible to think that such treatment may also have an effect in adiponectin levels.Objectives:To determine the short-term effect of the anti-IL-6 receptor tocilizumab (TCZ) administration on circulating adiponectin serum levels in patients with RA, as well as the potential association of adiponectin with demographic and clinical features of these patients.Methods:50 consecutive Spanish patients undergoing periodic treatment with TCZ who fulfilled the 2010 classification criteria for RA [5] were recruited. Adiponectin serum levels were assessed in samples obtained immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion) by a commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) kit.Results:Similar serum levels of adiponectin were found following the TCZ infusion (mean ± standard deviation: 23.01 ± 18.58 µg/mL versus 22.35 ± 17.84 µg/mL, pre- and post-infusion, respectively, p=0.69). Additionally, there was a negative correlation between adiponectin basal levels and body mass index (r=-0.45, pConclusion:Our study suggests that anti-IL-6 therapy has no short-term effect on adiponectin serum levels in patients with RA. Furthermore, our results support that low adiponectin levels are associated with MetS features and, therefore, with CV disease in RA.References:[1]Biochem Pharmacol. 2019;165:196-206; [2] Clin Exp Rheumatol. 2008;26:596-603; [3] Mediators Inflamm. 2013;2013:710928; [4] Clin Exp Rheumatol 2020;38:1201-1205; [5] Arthritis Rheum. 2010;62:2569-2581.Acknowledgements:Personal funds:SR-M: RD16/0012/0009 (ISCIII-ERDF); VP-C: PREVAL 18/01 (IDIVAL); OG: GPC IN607B2019/10 (GAIN); RL-M: Miguel Servet type I programme CP16/00033 (ISCIII-ESF).Disclosure of Interests:Sara Remuzgo-Martínez: None declared, Verónica Pulito-Cueto: None declared, Fernanda Genre: None declared, Jaime Calvo: None declared, Elena Aurrecoechea: None declared, Irene Llorente: None declared, Ana Triguero-Martinez: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Javier Llorca: None declared, M E Ruiz: None declared, Natalia Rivera: None declared, Oreste Gualillo: None declared, Raquel López-Mejías: None declared, Santos Castañeda: None declared, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD.

TAFRO syndrome is a rare variant type of multicentric Castleman disease, which is characterized by thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly. Here, we report a case of TAFRO syndrome that was successfully treated with tocilizumab. A 50-year-old man, who presented with fever, epigastric pain, abdominal fullness, and massive edema of the extremities, was admitted to our hospital. Computed tomography revealed bilateral pleural effusions, ascites, and lymphadenopathy. Laboratory data showed renal dysfunction, anemia, and thrombocytopenia. Examination of bone marrow and cervical lymph nodes led to a diagnosis of hyaline vascular-type Castleman disease. The level of serum interleukin (IL)-6 was extremely high. TAFRO syndrome was finally diagnosed. The patient was treated weekly with tocilizumab, an anti-IL-6 receptor antibody and steroids. In 4 weeks, all symptoms disappeared and serum IL-6 level returned to normal. Activity of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which was significantly decreased (9.9 %) prior to treatment, increased after treatment with tocilizumab. The present case suggests that tocilizumab is an effective therapeutic agent for TAFRO syndrome. We suggest that hypercytokinemia in TAFRO syndrome inhibits ADAMTS13 activity, thereby inducing thrombotic microangiopathy.

Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.

Background:Previously, 12-week results of phase 2 clinical study of levilimab (LVL) in patients with active rheumatoid arthritis (RA) have been reported1. The study has met the primary endpoint at W12 confirming that treatment with LVL 162 mg SC + methotrexate (MTX) either QW or Q2W is superior to MTX alone in patients with RA and inadequate response to methotrexate (MTX-IR). Here we report 1-year efficacy and safety data in QW and Q2W arm of the study.Objectives:This study was aimed to assess the efficacy and safety of 2 dosing regimens of LVL in active MTX-IR RA subjects.Methods:This multicenter double-blind placebo-controlled study (NCT03455842) enrolled 105 MTX-IR subjects with active RA (ACR2010). The study design is outlined on Figure 1. Secondary endpoints for the open-label period included ACR20/50/70, LDA, remission rates, and DAS28-CRP(4), among others. The safety was evaluated up to W56.Figure 1.Study designResults:At W12 ACR20 was reached by 77.1% and 57.1% of subjects of QW and Q2W arms respectively. Within open-label (OLE) period further increase in clinical response degree was observed up to W52, more pronounced in ACR50 and even more in ACR70 / RA LDA and Remission rates (Table 1). Figure 1 summarizes the dynamic of DAS28-CRP(4) change throughout the study. QW regimen showed better efficacy results.Table 1.Efficacy results (full analysis set), n (%).QW + MTX(n = 35)Q2W + MTX(n = 35)p-valueACR20 W1227 (77.1)20 (57.1)0.07 W5232 (91.4)25 (71.4)0.03ACR50 W1218 (51.4)11 (31.4)0.09 W5226 (74.3)23 (65.7)0.43ACR70 W1210 (28.6)7 (20.0)0.40 W5223 (65.7)16 (45.7)0.09LDA (DAS28 20 (57.1)10 (28.6)0.02 W5229 (82.9)24 (68.6)0.16EULAR Remission W244 (11.4)2 (5.7)0.67 W5210 (28.6)10 (28.6)1.00Table 2 shows the main safety endpoints for the entire study (W0 – W56). The most common treatment related AEs (registered >5% of subjects) were laboratory abnormalities (neutrophil count decrease, ALT / AST increase, blood cholesterol/triglycerides increased). SAE occurred within the blinded study period were reported previously1. During OLE, starting from W12, four new serious AE (SAEs) were reported: 3 in LVL QW arm: haemorrhage (gr.3, unrelated), vaginal cyst (gr.3, unrelated) and keratitis (gr.2, unrelated); 1 in LVL Q2W arm: myocardial ischemia with cardiovascular insufficiency (gr.5, unrelated).Table 2.Safety results (full analysis set, W0 – W56), n (%).QW + MTX(n = 35)Q2W + MTX(n = 35)Any TEAEs/SAEs34 (97.1)29 (82.9)Any SAEs4 (11.4)2 (5.7)Any gr. 3-4 AEs16 (45.7)12 (34.3)Gr. 3-4 neutropenia4 (11.4)5 (14.3)AEs of special interest(ALT / AST high; Leucopenia / Neutropenia; Infections; Cholesterol/triglycerides high)28 (80.0)26 (74.3)Treatment discontinuation due to AE04 (11.3)Deaths02 (5.7) (unrelated)Conclusion:Within 1 year of treatment LVL + MTX showed sustained efficacy, with continuous clinical improvement in MTX-IR subjects with active RA. The safety profile of LVL was consistent with other IL6R inhibitors. LVL QW regimen was shown to be safe with better efficacy in terms of time and magnitude and was selected for phase 3 confirmatory clinical study.References:[1]http://dx.doi.org/10.1136/annrheumdis-2019-eular.7220Figure 2.Absolute DAS-28-CRP(4) change (median ± IQR, full analysis set)Disclosure of Interests:V Mazurov: None declared, Evgeniy Zotkin: None declared, Elena Ilivanova Grant/research support from: JSC BIOCAD, Tatyana Kropotina Grant/research support from: JSC BIOCAD, Tatyana Plaksina Grant/research support from: JSC BIOCAD, Olga Nesmeyanova Grant/research support from: JSC BIOCAD, Nikolaj Soroka Grant/research support from: JSC BIOCAD, Alena Kundzer: None declared, Anton Lutskii Employee of: JSC BIOCAD, Ekaterina Dokukina Employee of: JSC BIOCAD, Anna Eremeeva Employee of: JSC BIOCAD, Arina Zinkina-Orihan Employee of: JSC BIOCAD

Cardiac mesenchymal stromal cells (cMSCs) comprise a significant portion of the human heart and have been shown to remodel in disease and secrete inflammatory cytokines. In previous studies we have seen that IL-6 is a potent inducer of Ca2+ mediated arrhythmia substrates in human myocytes. Though

A primary goal in the management of burn wounds is early wound closure. The use of skin allografts represents a lifesaving strategy for severe burn patients, but their ultimate rejection limits their potential efficacy and utility. IL-6 is a major pleiotropic cytokine which critically links innate and adaptive immune responses. Here, we devised anti-IL-6 receptor eluting gelatin methacryloyl (GelMA) biomaterials (GelMA/anti-IL-6), which were implanted at the interface between the wound beds and skin allografts. Our visible light crosslinked GelMA/anti-IL-6 immunomodulatory biomaterial (IMB) demonstrated a stable kinetic release profile of anti-IL-6. In addition, the incorporation of anti-IL-6 within the GelMA hydrogel had no effect on the mechanical properties of the hydrogels. Using a highly stringent skin transplant model, the GelMA/anti-IL-6 IMB almost doubled the survival of skin allografts. The use of GelMA/anti-IL-6 IMB was far superior to systemic anti-IL-6 receptor treatment in prolonging skin allograft survival. As compared to the untreated control group, skin from the GelMA/anti-IL-6 IMB group contained significantly fewer alloreactive T cells and macrophages. Interestingly, the environmental milieu of the draining lymph nodes (DLNs) of the mice implanted with the GelMA/anti-IL-6 IMB was also considerably less pro-inflammatory. The percentage of CD4+ IFNγ+ cells was much lower in the DLNs of the GelMA/anti-IL-6 IMB group in comparison to the GelMA group. These data highlight the importance of localized immune delivery in prolonging skin allograft survival and its potential utility in treating patients with severe burns.

[Background]McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop arthritis in the ankle, leading finally to ankylosis. There is no published data that drug treatment has been trialed on these mice.[Objectives]This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of ankylosis in McH-lpr/lpr-RA1 mice.[Methods]Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines.[Results]Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at every age. The kappa coefficient was 0.77. However, progression of ankylosis persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups.[Conclusions]Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for spondyloarthritis. IL6 signal blockade could contribute to the treatment of spondyloarthritis, and further studies should be carried out to confirm its potential in the prevention of deformity associated with ankylosis.

Background Systemic inflammation, insulin resistance (IR), and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA).1–3 In this regard, it has been described that the blockade of IL-6, a cytokine involved in the pathogenesis of both RA and atherosclerosis, yields a rapid improvement of endothelial function in RA.4 However, there are no studies on the role of anti-IL-6 treatment on IR in patients with RA. Objectives To assess whether IL-6 blockade may result in a reduction of insulin serum levels and an improvement of IR in patients with RA. Methods 50 Spanish patients on treatment with anti-IL-6 monoclonal antibody-Tocilizumab who fulfilled the 2010 classification criteria for RA5 were recruited. Patients with diabetes mellitus or plasma glucose >110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to (time 0) and after (time 60 min) Tocilizumab infusion. IR was assessed by the homeostasis model assessment (HOMA) and insulin sensitivity was evaluated by the quantitative insulin sensitivity check index (QUICKI). Results A marked reduction in the serum insulin levels was observed following Tocilizumab infusion (mean ±standard deviation (SD): 10.60±5.80 μU/ml versus 7.61±5.08 μU/ml, p Conclusions Our study confirms a rapid beneficial effect of Tocilizumab on IR and insulin sensitivity in RA patients treated with this drug. It may support the long-term use of drugs that act blocking IL-6 function to reduce the mechanisms implicated in the development of atherosclerosis in RA patients. References [1] Am J Med2003;114:647–652. [2] Autoimmun Rev2016;15:1013–1030. [3] Autoimmun Rev2004; 3:301–304. [4] Atherosclerosis2011;219:734–736. [5] Arthritis Rheum2010;62:2569–2581. Acknowledgements This study was supported by European Union FEDER funds and “Fondo de Investigacion Sanitaria” (PI15/00525) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Program RD16/0012 (RIER) from ISCIII, and in part by grants from the European IMI BTCure Program. SR-M is supported by funds of the RETICS Program (RIER) RD16/0012/0009 (ISCIII, co-funded by the European Regional Development Fund, ERDF). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, “Investing in your future”) (CP16/00033). FG is a recipient of a Sara Borrell post-doctoral fellowship from the ISCIII, co-funded by ESF (CD15/00095). VM is supported by funds of a Miguel Servet type I programme (CP16/00033) (ISCIII, co-funded by ERDF). Disclosure of Interest None declared

Background Development of biologics gives rise to novel classes of drugs, offering more options for treating children with primary or secondary failure of anti-TNF therapy. However, the question of whether or not previous exposure to biologic therapy and the number of previously administered biologics influence the efficacy of current treatment still needs to be solved. Objectives To compare tocilizumab efficacy in biologics-naive and biologics-switched patients with JIA. Methods Comparative analysis involved patients who had initiated TOC treatment at the National Medical Research Centre of Children’s Health (Moscow) depending on previous history of biologics therapy. Treatment efficacy was evaluated according to the dynamics of clinical and laboratory signs using the ACRPedi criteria. The Wallace criteria were used to evaluate whether or not remission had been achieved. Results Thirty-two patients were biologics-naive and 43 patients switched to TOC were previously treated with ETA (n=10), ADA (n=34), certolizumab (n=2), and infliximab (n=1). Children in the biologics-naive group differed from the switchers in a number of important baseline parameters: shorter disease duration (2.13 [1.25:5.34] and 7.42 [3:10.75] years, respectively; p 0.999). Conclusions Tocilizumab therapy is highly efficient both as the first and subsequent biologic agent. Children with history of therapy with at least one biologic agent have lower chances for achieving remission during the first 12 months of therapy. However, this difference is most likely caused by the longer and more severe arthritis course in children allocated to the group of biologics-switched patients compared to biologics-naive ones. Further matched large-cohort study is needed to identify predictors of response to therapy. Disclosure of Interest E. Alexeeva: None declared, T. Dvoryakovskaya Grant/research support from: Roche, Pfizer, M. Soloshenko: None declared, R. Denisova: None declared, K. Isaeva: None declared, A. Mamutova: None declared, V. Gladkikh: None declared, A. Moskalev: None declared

Background: Metabolic syndrome (MeS) is a pathologic state that encompasses metabolic anomalies such as hyperglycemia, dyslipidemia, obesity and hypertension and that, apart from being a cardiovascular risk factor, it has been associated with chronic inflammatory diseases such as rheumatoid arthritis (RA) 1,2 . Ghrelin and retinol binding protein-4 (RBP-4) are two biomarkers associated with MeS, and are also linked to different cardiometabolic risk factors. In this regard, it is known that ghrelin exerts an anti-inflammatory role, while RBP-4 has a pro-inflammatory role 2 . Objectives: Since a beneficial effect on endothelial function has been reported for anti-IL-6 therapy 3 , we aimed to evaluate the effect of a single infusion of anti-IL-6 on the serum levels of ghrelin and RBP-4 in patients with RA. Methods: Ghrelin and RBP-4 levels were measured in serum samples from 50 Spanish individuals with RA that fulfilled the 2010 classification criteria 4 , and that were under treatment with the anti-IL-6 monoclonal antibody Tocilizumab. Patients with diabetes mellitus or plasma glucose levels >110 mg/dL were excluded. Blood samples were taken in the fasting state, immediately before (time 0) and after (time 60 minutes) Tocilizumab infusion. Results: A significant increase in serum levels of ghrelin was observed after a single infusion of Tocilizumab (mean±standard deviation: 72.99±58.43 pg/mL versus 134.02±225.93 pg/mL, before and after Tocilizumab infusion, p=0.04). Serum levels of RBP-4 were not affected by the administration of Tocilizumab (mean±standard deviation: 23.48±13.99 μg/mL versus 20.90±15.54 μg/mL, before and after Tocilizumab infusion, p=0.42). Conclusions: Our results show that ghrelin levels increase after a single infusion of Tocilizumab, supporting the hypothesis that IL-6 blockade has a rapid beneficial effect on factors associated with MeS and cardiovascular risk in RA patients. Hence, long-term treatment with anti-IL-6 may reduce the risk of developing cardiovascular disease in RA. References [1] Best Pract Res Clin Rheumatol2016;30(5):851–869. [2] Biomed Res Int2014;2014:860651. [3] Atherosclerosis2011;219:734–36. [4] Arthritis Rheum2010;62:2569–81. Acknowledgements: FG is a recipient of a Sara Borrell post-doctoral fellowship from the Instituto de Salud Carlos III (ISCIII)(Spain), co-funded by European Social Fund (ESF,“Investing in your future”) (CD15/00095). SR-M is supported by funds of the RETICS Program (RIER) RD16/0012/0009 (ISCIII, co-funded by the European Regional Development Fund, ERDF). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (CP16/00033). VM is supported by funds of a Miguel Servet type I programme (CP16/00033)(ISCIII, co-funded by ERDF). Disclosure of Interest: None declared

Background BCD-089 is a fully human monoclonal antibody targeting membrane-bound and soluble forms of IL-6Rα, thereby blocking of IL-6 classic and trans- signalling. IL-6, a proinflammatory cytokine, plays a central role in the pathogenesis of many chronic inflammatory and autoimmune diseases. Thereby inhibition of IL-6 signalling is a promising approach in the treatment of immune-mediated pathology. Objectives To assess safety, immunogenicity, pharmacokinetics and pharmacodynamics of a single administration of BCD-089. Methods This was a phase I, open label, single ascending dose clinical study in healthy male volunteers, aged 22–37 years (n=19). In 1 st cohort, one «sentinel» volunteer received 0.006 mg/kg of BCD-089. Volunteers in cohorts 2–7 received single doses of BCD-089 0.3, 0.625, 1.0, 1.6, 2.2 and 2.9 mg/kg, respectively. Every next cohort was included after completed safety evaluation for the previous one. Safety, PK/PD and immunogenicity were assessed during 71 days follow up. Results All enrolled subjects have completed follow up period of 71 days. No withdrawals occurred. Single SC administration of BCD-089 was well tolerated and showed good safety profile at all tested doses: no grade 3/4 AEs, SAEs, DLTs or allergic reactions were reported in any cohort. None of the volunteers developed ADA to BCD-089. The only AEs reported were grade 1 or 2 laboratory abnormalities. Single SC administration of BCD-089 had a dose-dependent PK: the drug became detectable in the serum within the first 12 hour after injection for all tested doses (2–8 hour for doses>1.0 mg/kg). Serum concentration dose-proportionally increased and reached maximum at day 3 after administration, then gradually decreased. Elimination half-life showed significant inter-personal variability and dose-dependency, reflecting non-linear PK typical for drugs with target-mediated disposition. The concentration of soluble IL-6 receptor increased after BCD-089 administration in a dose-dependent manner. A raise in the concentration of IL-6 was seen at doses>1.0 mg/kg. Membrane IL-6R saturation of 90%>100% was seen at doses≥0.6 mg/kg. Regardless to the dose, serum CRP decreased below the limit of detection in most volunteers within the first week after injection. All tested PD markers returned to baseline at the end of the follow-up. Conclusions Single SC administration of BCD-089 was well tolerated, showed favourable safety profile and low immunogenicity at all tested doses in healthy volunteers. PK/PD assessment revealed non-linear PK and significant capacity to inhibit the IL-6 signalling pathway. These finding supports further clinical development of BCD-089. Disclosure of Interest P. Khlyabova: None declared, A. Eremeeva Employee of: JSC BIOCAD, A. Lutckii Employee of: JSC BIOCAD, E. Dokukina Employee of: JSC BIOCAD, E. Chernyaeva Employee of: JSC BIOCAD, R. Ivanov Employee of: JSC BIOCAD

Background: Leptin is an adipocytokine that plays an important role in the regulation of body weight and also participates both in immune homeostasis and inflammatory processes [1,2]. Chronic systemic inflammation is of major importance in the development of atherosclerosis in rheumatoid arthritis (RA) [3]. IL-6 blocker yields a rapid improvement of endothelial function [4]. Objectives: To determine whether the infusion of IL-6 blockade improves the endothelial function by altering circulating Leptin concentrations in patients with RA. Methods: 50 Spanish patients on treatment with anti-IL-6 monoclonal antibody-Tocilizumab who fulfilled the 2010 classification criteria for RA [5] were recruited. Patients with diabetes mellitus or plasma glucose >110 mg/dl were excluded. Leptin serum levels were determined immediately prior to (time 0) and after (time 60 minutes) Tocilizumab infusion by Enzyme-Linked ImmunoSorbent Assay (ELISA). Results: A significant reduction in Leptin concentration was observed following Tocilizumab infusion (mean±standard deviation (SD): 9.24±7.98 ng/ml versus 7.91±7.36 ng/ml, px0.0011). In addition, a significant positive correlation between Leptin concentration and insulin resistance (HOMA at the time of the study) was found (r= 0.40; p=0.0046). Furthermore, a significant negative correlation between Leptin levels and insulin sensitivity (QUICKI) was disclosed (r= -0.46; p=0.0009). Conclusions: Our study confirms that circulating Leptin concentrations are modulated by anti-IL-6 treatment. In addition, Leptin concentration correlates with insulin resistance and sensitivity. The beneficial effect of anti-IL-6 blockage on cardiovascular mortality in RA may be mediated by reduction in serum levels of leptin. References 1] Nat Rev Immunol2006;6:772–83. 2] Nat Rev Immunol2006;6:772–83. 3] Autoimmun Rev2016;15:1013–30. 4] Atherosclerosis2011;219:734–6. 5] Arthritis Rheum2010;62:2569–81. Acknowledgements: This study was supported by European Union FEDER funds and “Fondo de Investigacion Sanitaria” (PI15/00525) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Program RD16/0012 (RIER) from the ISCIII, and in part by grants from the European IMI BTCure Program. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, “Investing in your future”) (CP16/00033). FG is a recipient of a Sara Borrell post-doctoral fellowship from the ISCIII, co-funded by ESF (CD15/00095). SR-M is supported by funds of the RETICS Program (RIER) RD16/0012/0009 (ISCIII, co-funded by the European Regional Development Fund, ERDF). VM is supported by funds of a Miguel Servet type I programme (CP16/00033) (ISCIII, co-funded by ERDF). Disclosure of Interest: None declared

Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro. We evaluated the safety, pharmacokinetics, immunogenicity, and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. This open-label, phase 1, dose-escalating study used two doses of siltuximab: 5.5 and 11.0 mg/kg (administered on day 1 of each 21-day cycle). In total, nine patients were treated. The most common grade 3/4 adverse events, lymphopenia (89 %) and thrombocytopenia (44 %), occurred in patients receiving both doses of siltuximab; however, no dose-limiting toxicities (DLTs) were observed. Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg, the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner. Mean half-life, total systemic clearance, and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg. Across both doses, six of the nine patients had complete or partial response (22 and 44 %, respectively). In conclusion, as no DLT was observed, the recommended dose for this combination is 11.0 mg/kg once every 3 weeks. The study is registered at http://www.clinicaltrials.gov as NCT01309412.

Background Sirukumab is an anti–interleukin-6 (IL-6) monoclonal antibody that selectively binds to the cytokine with high affinity and is in development for rheumatoid arthritis (RA) and other diseases. Objectives This study evaluated the effects of sirukumab on work productivity/interference and health status in patients with active RA despite treatment with anti-tumor necrosis factor (TNF) therapy. Methods In this randomized, double-blind, phase 3 trial, 878 eligible patients with active RA who were intolerant/refractory to anti-TNFs were randomized 1:1:1 to sirukumab subcutaneous (SC) 50mg every 4 weeks (q4w; n=292), sirukumab SC 100mg every 2 weeks (q2w; n=292), or placebo SC q2w (n=294). At Week 18, placebo patients were re-randomized to 1 of the sirukumab doses if insufficient ( Results At Week 24, mean total WLQ scores improved significantly from baseline for sirukumab 50mg q4w and 100mg q2w versus placebo (mean change, –2.2 and –2.3 vs 0.2, respectively; both p Conclusions Sirukumab treatment led to significant improvements in work-related productivity and general health status in patients with active RA despite anti-TNF therapy, consistent with demonstrated effects of sirukumab on RA disease improvement. Disclosure of Interest Y. Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Takeda, Speakers bureau: Abbvie, Asahi Kasei, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Pfizer, Sanofi, Takeda, Teijin, YL Biologics, D. Aletaha Grant/research support from: AbbVie, Pfizer, Grunenthal, Merck, Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche, Consultant for: AbbVie, Pfizer, Grunenthal, Merck, Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche, S. Peterson Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Ganguly Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, R. Kurrasch Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, S. Popik Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, P. Agarwal Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, N. Li Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Contains fulltext : 173198.pdf (Publisher’s version ) (Open Access) Th17 cells and their cytokines are linked to the pathogenesis of rheumatoid arthritis, a chronic autoimmune disease characterized by joint inflammation. Th17 development is initiated by combined signaling of TGF-beta and IL-6 or IL-21, and can be reduced in the absence of either IL-6 or IL-21. The aim of this study was to assess whether combinatorial IL-6/IL-21 blockade would more potently inhibit Th17 development, and be more efficacious in treating arthritis than targeting either cytokine. We assessed in vitro Th17 differentiation efficacy in the absence of IL-6 and/or IL-21. To investigate in vivo effects of IL-6/IL-21 blockade on Th17 and arthritis development, antigen-induced arthritis (AIA) was induced in IL-6-/- x IL-21R-/- mice. The therapeutic potential of this combined blocking strategy was assessed by treating mice with collagen-induced arthritis (CIA) with anti-IL-6R antibodies and soluble (s)IL-21R.Fc. We demonstrated that combined IL-6/IL-21 blocking synergistically reduced in vitro Th17 differentiation. In mice with AIA, absence of IL-6 and IL-21 signaling more strongly reduced Th17 levels and resulted in stronger suppression of arthritis than the absence of either cytokine. Additionally, anti-IL-6/anti-IL-21 treatment of CIA mice during the arthritis induction phase reduced disease development more potent than IL-6 or IL-21 inhibition alone, as effective as anti-TNF treatment. Collectively, these results suggest dual IL-6/IL-21 inhibition may be a more efficacious therapeutic strategy compared to single cytokine blockade to suppress arthritis development.

We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.

To evaluate the safety and efficacy of a humanized anti-interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).Seven patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells.Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations.Interleukin-6 receptor blockade is a promising therapeutic option for NMO.This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.

Purpose: To evaluate the safety and pharmacokinetics of siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Results: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR.