No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors
Abstract
Objective:
To evaluate long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFi).
Methods:
Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) whoreceived double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventionalsynthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w pluscsDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratoryabnormalities and clinical disease activity scores. All statistics are descriptive.
Results:
Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. Cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidencerates per 100 PY of AEs, AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). Absoluteneutrophil count <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and between patients who either remained on 200mg or reduced to 150 mg.
Conclusion:
In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5years.
... Consequently ILmediated signaling and its pro-inflammatory effects are suppressed. [185][186][187][188][189][190][191] (IL-1: i.e., Anakinra, IL-6: i.e., Tocilizumab, Sarilumab, IL- 17: i.e., Secukinumab, IL-21 Abs) CXCL chemokine inhibitors Inhibition of chemokines and chemokine receptors, which are found in inflamed synovia, to reduce the synovial migration of B-cells and the formation of ectopic germinal centers. [192,193] (i.e., CXCL-10, -12, -13) ...
... Despite studies demonstrating evidence of inhibition of tissue destruction and improvement of clinical symptoms in RA patients by IL-inhibitor administration and its clinical effectiveness, studies also showed lower efficacy compared to TNFi [186,261,264]. Moreover, common side effects during treatment with IL inhibitors include, for example, urinary and respiratory tract infections, neutropenia, or erythema at the injection site [187,188]. ...
Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. While patients show very individual courses of disease, with RA focusing on the musculoskeletal system, joints are often severely affected, leading to local inflammation, cartilage destruction, and bone erosion. To prevent joint damage and physical disability as one of many symptoms of RA, early diagnosis is critical. Auto-antibodies play a pivotal clinical role in patients with systemic RA. As biomarkers, they could help to make a more efficient diagnosis, prognosis, and treatment decision. Besides auto-antibodies, several other factors are involved in the progression of RA, such as epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells. Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. In this review, the latest RA research findings are discussed to better understand the pathogenesis, and finally, treatment strategies for RA therapy are presented, including both conventional approaches and new methods that have been developed in recent years or are currently under investigation.
... After a follow-up of 5 years, safety profile of sarilumab in RA refractory to TNFi remained unchanged. The most frequent adverse events were neutropenia with an incidence of 15.3 cases per 100 patients-years (PY) [229]. The incidence of serious infection was 3.9 per 100 PY, comparable to other bDMARDs. ...
... Increase risk of serious bacterial infections, skin and soft tissue infections, and diverticulitis. Rare opportunistic infections (TB, fungi) [229,230]. ...
Interleukin (IL)-6 is produced locally in response to an inflammatory stimulus, and is able to induce systemic manifestations at distance from the site of inflammation. Its unique signaling mechanism, including classical and trans-signaling pathways, leads to a major expansion in the number of cell types responding to IL-6. This pleiotropic cytokine is a key factor in the pathogenesis of rheumatoid arthritis (RA) and is involved in many extra-articular manifestations that accompany the disease. Thus, IL-6 blockade is associated with various biological effects beyond the joints. In this review, the systemic effects of IL-6 in RA comorbidities and the consequences of its blockade will be discussed, including anemia of chronic disease, cardiovascular risks, bone and muscle functions, and neuro-psychological manifestations.
... However, all cohorts (based on progressively restrictive inclusion criteria) demonstrated treatment effectiveness, and there was no impact of calendar year on the treatment response; this highlights the well-established efficacy of sarilumab in patients with RA [1,3,38,39]. Furthermore, the greatest improvements were seen in the cohort that had the highest baseline CDAI score and mirrored the phase 3 trial population in TNFi inadequate responders, consistent with the literature evidence [2,42,43]. This could be due to the more selective nature of the clinical trial population, in which better treatment responses are noted than the real-world setting [13,[15][16][17]. ...
Introduction:
Clinical trial findings may not be generalizable to routine practice. This study evaluated sarilumab effectiveness in patients with rheumatoid arthritis (RA) and tested the real-world applicability of a response prediction rule, derived from trial data using machine learning (based on C-reactive protein [CRP] > 12.3 mg/l and seropositivity [anticyclic citrullinated peptide antibodies, ACPA +]).
Methods:
Sarilumab initiators from the ACR-RISE Registry, with ≥ 1 prescription on/after its FDA approval (2017-2020), were divided into three cohorts based on progressively restrictive criteria: Cohort A (had active disease), Cohort B (met eligibility criteria of a phase 3 trial in RA patients with inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi]), and Cohort C (characteristics matched to the phase 3 trial baseline). Mean changes in Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) were evaluated at 6 and 12 months. In a separate cohort, predictive rule was tested based on CRP levels and seropositive status (ACPA and/or rheumatoid factor); patients were categorized into rule-positive (seropositive with CRP > 12.3 mg/l) and rule-negative groups to compare the odds of achieving CDAI low disease activity (LDA)/remission and minimal clinically important difference (MCID) over 24 weeks.
Results:
Among sarilumab initiators (N = 2949), treatment effectiveness was noted across cohorts, with greater improvement noted for Cohort C at 6 and 12 months. Among the predictive rule cohort (N = 205), rule-positive (vs. rule-negative) patients were more likely to reach LDA (odds ratio: 1.5 [0.7, 3.2]) and MCID (1.1 [0.5, 2.4]). Sensitivity analyses (CRP > 5 mg/l) showed better response to sarilumab in rule-positive patients.
Conclusions:
In real-world setting, sarilumab demonstrated treatment effectiveness, with greater improvements in the most selective population, mirroring phase 3 TNFi-refractory and rule-positive RA patients. Seropositivity appeared a stronger driver for treatment response than CRP, although optimization of the rule in routine practice requires further data.
... In addition, IL-6-mediated JAK/STAT3 signaling is essential for osteoclastogenesis, Th17 differentiation, and chronic inflammation and has a crucial effect on the development of RA (29)(30)(31). The JAK inhibitor tofacitinib and IL-6 inhibitor sarilumab have been used for the treatment of various autoimmune diseases, such as RA (32)(33)(34). ...
Nuclear-factor, interleukin 3 regulated (NFIL3) is an immune regulator that plays an essential role in autoimmune diseases. However, the relationship between rheumatoid arthritis (RA) and NFIL3 remains largely unknown. In this study, we examined NFIL3 expression in RA patients and its potential molecular mechanisms in RA. Increased NFIL3 expression levels were identified in peripheral blood mononuclear cells (PBMCs) from 62 initially diagnosed RA patients and 75 healthy controls (HCs) by quantitative real-time PCR (qRT-PCR). No correlation between NFIL3 and disease activity was observed. In addition, NFIL3 expression was significantly upregulated in RA synovial tissues analyzed in the Gene Expression Omnibus (GEO) dataset (GSE89408). Then, we classified synovial tissues into NFIL3-high (≥75%) and NFIL3-low (≤25%) groups according to NFIL3 expression levels. Four hundred five differentially expressed genes (DEGs) between the NFIL3-high and NFIL3-low groups were screened out using the “limma” R package. Enrichment analysis showed that most of the enriched genes were primarily involved in the TNF signaling pathway via NFκB, IL-17 signaling pathway, and rheumatoid arthritis pathways. Then, 10 genes (IL6, IL1β, CXCL8, CCL2, PTGS2, MMP3, MMP1, FOS, SPP1, and ADIPOQ) were identified as hub genes, and most of them play a key role in RA. Positive correlations between the hub genes and NFIL3 were revealed by qRT-PCR in RA PBMCs. An NFIL3-related protein–protein interaction (PPI) network was constructed using the STRING database, and four clusters (mainly participating in the inflammatory response, lipid metabolism process, extracellular matrix organization, and circadian rhythm) were constructed with MCODE in Cytoscape. Furthermore, 29 DEGs overlapped with RA-related genes from the RADB database and were mainly enriched in IL-17 signaling pathways. Thus, our study revealed the elevated expression of NFIL3 in both RA peripheral blood and synovial tissues, and the high expression of NFIL3 correlated with the abnormal inflammatory cytokines and inflammatory responses, which potentially contributed to RA progression.
... The data from these trials suggest that its safety and tolerability profiles are consistent across studies and comparable with tocilizumab, with no new safety signals emerging. 165 This is different from sirukumab, a direct inhibitor of the IL-6 cytokine, which was not approved by the FDA in 2017 because of a numerically higher mortality rate among patients treated with sirukumab compared with controls. 166 167 Cardiovascular events, infections and malignancies were the most common causes of mortality. ...
Background:
Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.
Methods:
A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.
Results:
The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.
Conclusions:
The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.
... В исследовании AMBITION было продемонстрировано превосходство монотерапии тоцилизумабом над монотерапией метотрексатом у больных, ранее не получавших метотрексат [21,22]. В исследованиях сарилумаба MOBILITY [23], TARGET [24], MONARCH [25] были получены аналогичные результаты. Они подтвердили возможность применения препарата в виде монотерапии [26][27][28]. ...
The inhibitors of the biological effects of interleukin 6 (IL-6) are the most actively developing group of biologics for the treatment of rheumatoid arthritis (RA) due to pleiotropic effects of this most important pro-inflammatory cytokine, which stimulates a number of processes that play an important role in the pathogenesis of RA. IL-6 receptor (IL-6R) is of great importance in the implementation of these biological effects. Activation of IL-6R occurs with the participation of the glycoprotein gp130 in three variants: classical, and in trans-signaling and trans-presentation modes. The most recent representative of this group is levilimab, an IgG1 monoclonal antibody to IL-6R that binds both soluble and membrane forms of the receptor. The efficacy and safety of levilimab has been demonstrated in the Phase II AURORA and Phase III SOLAR trials. The paper presents the main statements of the resolution of the regional expert council of rheumatologists of Moscow and the Moscow Region on the topic: ‘The place of a new IL-6R inhibitor levilimab in the treatment of patients with rheumatoid arthritis’, which took place on December 18, 2021 in Moscow. The panel of experts confirmed that levilimab is recommended for widespread use in patients with active RA who fail or are intolerant to traditional synthetic DMARDs.
... In this issue of Rheumatology, Fleischmann et al. [1] published the 5 year follow-up results of the EXTEND trial (NCT01146652), in which long-standing RA patients with an inadequate response or intolerance (IR) to TNF inhibitors (TNFis) received sarilumab 200 mg every 2 weeks plus conventional synthetic DMARDs (csDMARDs). This is the open-label extension (OLE) of the TARGET trial (NCT01709578) in which sarilumab 150 or 200 mg every 2 weeks plus csDMARDs was compared with placebo plus csDMARDs in the same population. ...
Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.
Introdução: A artrite reumatoide (AR) é uma doença autoimune crônica e debilitante que afeta milhões de pessoas em todo o mundo. Objetivo: Identificar por meio da literatura científica quais são os avanços no tratamento da artrite reumatoide, incluindo as terapias alvo e modificações no curso da doença. Métodos: Trata-se de uma revisão integrativa da literatura por proporcionar uma síntese dos resultados obtidos através de pesquisas publicadas. Para direcionar a pesquisa, adotou-se como pergunta norteadora: “O que a literatura científica dispõe acerca dos avanços no tratamento da artrite reumatoide?" Para construção da pesquisa, a coleta e análise de dados foram realizadas através do Portal da Biblioteca Virtual da Saúde , base de dados Medical Literature Analysis and Retrievel System Online via PubMed e Google Scholar, através dos Descritores em Ciências da Saúde (DeCS): “Terapêutica”, “Artrite Reumatoide” e “Diagnóstico” combinados entre si pelo operador booleano AND. Discussão: Os avanços no tratamento da artrite reumatoide têm proporcionado melhorias na qualidade de vida dos pacientes. As terapias alvo de atenção como uma abordagem revolucionária no controle da doença, especificamente as que utilizam as células envolvidas no processo inflamatório. Essas terapias têm se mostrado altamente eficazes, atendendo a atividade da artrite e retardando o progresso da doença. Conclusão: Os avanços no tratamento da artrite reumatoide, com enfoque nas terapias alvo e modificações no curso da doença, têm sido revolucionários na abordagem desta condição crônica debilitante. O surgimento das terapias alvo, especialmente os inibidores do fator de necrose tumoral e da interleucina 6, tem proporcionado resultados impressionantes.
Objectives:
To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).
Methods:
SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.
Results:
Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.
Conclusion:
The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.
Treatment options for various rheumatologic diseases have been limited until the introduction of biologic agents and kinase inhibitor therapy in recent decades. Since their arrival, they have steadily been integrated into routine management. Given their wide use and overall successful outcomes, it becomes increasingly pertinent for clinicians to readily identify their side effects. Their effects can involve multiple organ systems, including hematologic. This review aims to identify and classify the range of hematologic effects associated with individual biologics and kinase inhibitors used for treatment of rheumatologic diseases.
Introduction:
Rheumatoid arthritis (RA) pathogenesis is driven by a complex network of proinflammatory cytokines, among which interleukin-6 (IL-6) plays a key role in inducing and perpetuating chronic inflammation. Targeting the IL-6 pathway has shown to be an invaluable treatment strategy, as demonstrated by the results accrued in the last decade with the first IL-6 inhibitor, tocilizumab. More recently, a second monoclonal antibody blocking IL-6, sarilumab, has enriched our armamentarium by proving outstanding efficacy in RA treatment.
Areas covered:
After exploring the IL-6 pathway under physiological conditions and in the RA pathogenesis, in this review we discuss the pharmacologic properties of sarilumab and the clinical trials that constitute the sarilumab development program and have enabled its licensed application.
Expert opinion:
Results from clinical trials confirmed the efficacy and safety of sarilumab for the treatment of RA, similar to its precursor tocilizumab. Blocking IL-6 pathway results in comprehensive control of the disease, from both physician's and patient's perspective, and of RA comorbidities and extra-articular manifestations which are largely IL-6 driven. Finally, the proven efficacy of sarilumab as monotherapy arises the drug as a required therapeutic alternative considering the large proportion of patients intolerant or inadequate to receive conventional synthetic disease-modifying drugs (csDMARDs).
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 non‐circulating 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, 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 assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept.
Methods
This randomized, open‐label, parallel‐group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open‐label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group.
Results
By week 4 of treatment, the serum low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow‐up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77–1.43). Results were similar in sensitivity analyses and in the on‐treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation.
Conclusion
The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non‐CV safety of tocilizumab.
Objective
In MOBILITY ( NCT01061736 ), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate. We report 5-year safety, efficacy and radiographic outcomes of sarilumab from NCT01061736 and the open-label extension (EXTEND; NCT01146652 ), in which patients received sarilumab 200 mg every 2 weeks (q2w) + methotrexate.
Methods
Patients (n=1197) with moderately to severely active RA were initially randomised to placebo, sarilumab 150 mg or sarilumab 200 mg subcutaneously q2w plus weekly methotrexate for 52 weeks. Completers were eligible to enrol in the open-label extension and receive sarilumab 200 mg q2w + methotrexate.
Results
Overall, 901 patients entered the open-label extension. The safety profile remained stable over 5-year follow-up and consistent with interleukin-6 receptor blockade. Absolute neutrophil count <1000 cells/mm ³ was observed but not associated with increased infection rate. Initial treatment with sarilumab 200 mg + methotrexate was associated with reduced radiographic progression over 5 years versus sarilumab 150 mg + methotrexate or placebo + methotrexate (mean±SE change from baseline in van der Heijde-modified Total Sharp Score: 1.46±0.27, 2.35±0.28 and 3.68±0.27, respectively (p<0.001 for each sarilumab dose versus placebo)). Clinical efficacy was sustained through 5 years according to Disease Activity Score (28-joint count) using C reactive protein, Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index. The number of patients achieving CDAI ≤2.8 at 5 years was similar among initial randomisation groups (placebo, 76/398 (19%); sarilumab 150 mg, 68/400 (17%); sarilumab 200 mg, 84/399 (21%)).
Conclusion
Clinical efficacy, including inhibition of radiographic progression, reduction in disease activity and improvement in physical function, was sustained with sarilumab + methotrexate over 5 years. Safety appeared stable over the 5-year period.
Objective:
Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions.
Methods:
Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed.
Results:
2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time.
Conclusion:
The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.
Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA).
Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-methotrexate csDMARDs for 52 weeks. The primary endpoint was safety.
Results: Sixty-one patients received monotherapy (S150, n = 30; S200, n = 31) and 30 received combination therapy (S150 + csDMARDs, n = 15; S200 + csDMARDs, n = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + csDMARDs group. There were no cases of Grade 4 neutropenia; no patients with Grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (HAQ-DI) and DAS28-CRP were observed at Weeks 24 and 52 (all groups).
Conclusions: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/symptoms and physical function in Japanese RA patients.
Objective
Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study.
Methods
In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks’ double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v.
Results
In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study.
Conclusion
No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab.
Trial registration numbers
ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).
Objectives:
To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR).
Methods:
In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator's discretion.
Results:
Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years.
Conclusion:
Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.
Introduction
To examine treatment persistence and clinical outcomes associated with switching from a tumor necrosis factor inhibitor (TNFi) to a medication with a new mechanism of action (MOA) (abatacept, anakinra, rituximab, tocilizumab, or tofacitinib) versus cycling to another TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) among patients with rheumatoid arthritis.
Methods
This retrospective, longitudinal study included patients with rheumatoid arthritis in the JointMan® US clinical database who received a TNFi in April 2010 or later and either cycled to a TNFi or switched to a new MOA therapy by March 2015. Cox proportional hazards models were used for time to non-persistence (switching or discontinuing). An ordinary least squares regression model compared 1-year reduction from baseline for the Clinical Disease Activity Index (CDAI).
Results
There were 332 (54.2%) TNFi cyclers and 281 (45.8%) new MOA switchers. During a median follow-up of 29.9 months, treatment persistence was 36.7% overall. Compared with new MOA switchers, TNFi cyclers were 51% more likely to be non-persistent (adjusted hazard ratio, 1.511; 95% CI 1.196, 1.908), driven by a higher likelihood of switching again (adjusted hazard ratio, 2.016; 95% CI 1.428, 2.847). Clinical outcomes were evaluable for 239 (53.3%) TNFi cyclers and 209 (46.7%) new MOA switchers. One-year mean reduction in CDAI from baseline to end of follow-up was significantly higher for new MOA switchers than TNFi cyclers (−7.54 vs. −4.81; P = 0.037), but the difference was not statistically significant after adjustment for baseline CDAI (−6.39 vs. −5.83; P = 0.607).
Conclusion
In this study, TNFi cycling was common in clinical practice, but switching to a new MOA DMARD was associated with significantly better treatment persistence and a trend toward greater CDAI reduction that was not significant after adjustment for baseline disease activity.
Funding
Sanofi and Regeneron Pharmaceuticals.
Objective:
While tocilizumab (TCZ) is known to increase LDL cholesterol, it is unclear whether TCZ increases cardiovascular (CV) risks in patients with rheumatoid arthritis (RA).
Methods:
To examine comparative CV safety, we conducted a cohort study of RA patients who newly started TCZ or TNFi using claims data from Medicare, IMS PharMetrics and MarketScan. All patients were required to have previously used a different TNFi, abatacept, or tofacitinib. The primary outcome was a composite CV endpoint of hospitalization for myocardial infarction (MI) or stroke. TCZ initiators were propensity score (PS) matched to TNFi initiators with a variable ratio of 1:3 within each database controlling for >65 baseline characteristics. A fixed-effects model combined database-specific hazard ratios (HR).
Results:
We included 9,218 TCZ initiators PS-matched to 18,810 TNFi initiators across all three databases. Mean age was 72 years in Medicare, 51 in PharMetrics and 53 in MarketScan. 14.3% of TCZ initiators and 13.5% of TNFi had baseline CV disease. During the study period (mean±SD: 0.9±0.7 years, maximum: 4.5 years), 125 composite CV events occurred resulting in the incidence rate of 0.52 per 100 person-years in TCZ initiators and 0.59 per 100 person-years among TNFi initiators. The risk of CV events associated with TCZ use versus TNFi was similar across all three databases with a combined HR of 0.84 (95%CI 0.56-1.26).
Conclusion:
This multi-database population-based cohort study found no evidence of an increased CV risk among RA patients who switched from a different biologic drug or tofacitinib to TCZ versus to a TNFi. This article is protected by copyright. All rights reserved.
Objective:
To evaluate efficacy and safety of sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with active, moderate-to-severe rheumatoid arthritis (RA) with inadequate response or intolerance to anti-tumor necrosis factor (TNF) therapies.
Methods:
Patients were randomly allocated to receive sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks (q2w) for 24 weeks with background csDMARD(s). Coprimary endpoints were proportion of patients achieving American College of Rheumatology 20% (ACR20) response at week 24 and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 12. Each sarilumab dose was evaluated against placebo; differences between the 2 sarilumab doses were not assessed.
Results:
Baseline characteristics were similar among treatment groups. ACR20 response rate at week 24 was significantly higher with sarilumab 150 and 200 mg q2w compared with placebo (55.8%, 60.9% vs 33.7%; P<0.0001). Mean change from baseline in HAQ-DI score at week 12 was significantly greater with sarilumab (least squares mean change, 150 mg: -0.46 [P=0.0007]; 200 mg: -0.47 [P=0.0004]) vs placebo (-0.26). Infections were the most frequently reported treatment-emergent adverse events. Serious infections occurred in 1.1%, 0.6%, and 1.1% of patients receiving placebo, sarilumab 150 mg, and sarilumab 200 mg, respectively. Laboratory abnormalities included decreased absolute neutrophil count (ANC) and increased transaminases. In this study, reductions in ANC were not associated with increased incidence of infections or serious infections.
Conclusion:
Sarilumab 150 and 200 mg q2w plus csDMARD(s) improved signs and symptoms of RA and physical function in patients with inadequate response or intolerance to anti-TNFs. Safety data were consistent with interleukin 6 receptor blockade and the known safety profile of sarilumab. This article is protected by copyright. All rights reserved.
Objectives:
To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.
Methods:
MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.
Results:
Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.
Conclusions:
Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.
Trial registration number:
NCT02332590.
Objectives. To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for treatment of rheumatoid arthritis (RA). Methods. Adults with moderate-to-severe RA and inadequate response to MTX were randomized (1:1:1) to sarilumab 150mg, 200 mg, or placebo every 2 weeks (q2w) with MTX for 52 weeks. Results. Baseline characteristics were similar among groups. For all three co-primary endpoints, sarilumab 150mg and 200mg groups demonstrated statistically significant improvements vs placebo: ACR20 response at Week 24 (58.0%, 66.4% vs 33.4%; p<0.0001), HAQ-DI at Week 16 (-0.53, -0.55, vs -0.29; p<0.0001) and mTSS at Week 52 (0.90, 0.25 vs 2.78; p<0.0001). The most common treatment-emergent adverse event was infection; serious infections incidence was 2.6%, 4.0%, and 2.3% (sarilumab 150mg, 200 mg, and placebo, respectively). Elevations in alanine aminotransferase >3-fold the upper limit of normal in 9.5%, 8.0%, and 2.1% of patients led to discontinuation of 24 patients. Elevated total cholesterol levels were observed in 36.8%, 43.0% and 18.3% of sarilumab 150mg, 200 mg and placebo patients, respectively. Neutrophil counts 500-<1000 Giga/L occurred in 5.1% and 7.8%, <500 Giga/L in 0.9% and 0.7% of sarilumab 150mg and 200mg patients, respectively, and none receiving placebo. Conclusions: In RA patients treated with sarilumab (150mg and 200mg q2w) in combination with MTX, both doses provided sustained clinical efficacy, significantly improving symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with IL-6 signaling blockade. This article is protected by copyright. All rights reserved.
© 2015 American College of Rheumatology.
The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy.
In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts.
The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm).
Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors.
NCT00718718.
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol.
This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org).
The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
Interleukin (IL)-6, a cytokine featuring redundancy and pleiotropic activity, contributes to host defense against acute environmental stress, while dysregulated persistent IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases. Targeting IL-6 is thus a rational approach to the treatment of these diseases. Indeed, clinical trials of tocilizumab, a humanized anti-IL-6 receptor antibody have verified its efficacy and tolerable safety for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for treatment of these diseases. Moreover, a considerable number of case reports and pilot studies of off-label use of tocilizumab point to the beneficial effects of tocilizumab for a variety of other phenotypically different autoimmune and chronic inflammatory diseases. Elucidation of the source of IL-6 and of mechanisms through which IL-6 production is dysregulated can thus be expected to lead to clarification of the pathogenesis of various diseases.
Inflammatory rheumatic diseases are generally multifaceted disorders and, therefore, measurement of multiple outcomes is relevant to most of these diseases. Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Outcome measurement will increasingly deal with measurement of low levels of disease activity and avoidance of disease consequences. It is an advantage for patient management and knowledge transfer if the same outcomes are used in practice and in trials. Continuous measures of change are generally the most powerful and, therefore, are preferred as primary outcomes in trials. For daily clinical practice, outcome measures should reflect the patients' state and have to be easily derivable. The objective of this review is to describe recent developments in outcome measures for inflammatory rheumatic diseases for trials and clinical practice, with an emphasis on rheumatoid arthritis.
The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.
499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.
ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.
Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.
NCT00106522.
IL-6 is a pleiotropic cytokine involved in many biological functions that affect tissues beyond the immune system and the vasculature. This multifunctional cytokine exerts its actions via the classic signalling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or via the trans-signalling pathway upon binding to the soluble form of IL-6R (sIL-6R). In general, classic IL-6 signalling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signalling is responsible for the pro-inflammatory actions of IL-6. As a result, dysregulation of the IL-6 axis can lead to the onset or development of several disease states, particularly autoimmune and inflammatory disorders, including RA and GCA. This pathological role of IL-6 means that pharmacologic modulation of the IL-6 axis is a rational therapeutic approach; however, multiple predictable, but often underappreciated, effects on tissues and organs beyond the blood vessels may also occur. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
Background Decreases in circulating neutrophils (polymorphonuclear leukocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and / or bone marrow trafficking without affecting neutrophil function or apoptosis. Materials and methods 18 healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labeled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count. Results Mean day 4 neutrophil counts, as % baseline, were 101.9%, 68.3% and 44.2% in the placebo, TCZ-PMN-’high’ and TCZ-PMN-’low’ groups, respectively (p < 0.001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver / spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs 127% TCZ-PMN-low, p < 0.001; day 10, 180% placebo vs 132% TCZ-PMN-low, p < 0.01), with a trend towards higher liver / spleen neutrophil retention. Conclusions We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity.
Background:
Decreases in circulating neutrophils (polymorphonuclear leukocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and / or bone marrow trafficking without affecting neutrophil function or apoptosis.
Materials and methods:
18 healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labeled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count.
Results:
Mean day 4 neutrophil counts, as % baseline, were 101.9%, 68.3% and 44.2% in the placebo, TCZ-PMN-'high' and TCZ-PMN-'low' groups, respectively (p < 0.001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver / spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs 127% TCZ-PMN-low, p < 0.001; day 10, 180% placebo vs 132% TCZ-PMN-low, p < 0.01), with a trend towards higher liver / spleen neutrophil retention.
Conclusions:
We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity. This article is protected by copyright. All rights reserved.
Rheumatoid arthritis (RA) is considered a chronic disease that cannot be cured. Biologic agents have enabled good therapeutic successes; however, the response to biologic therapy depends on treatment history and, especially, disease duration. In general, the more drug-experienced the patients, the lower the response rates, although this limitation can be overcome by promptly adjusting or switching treatment in a treat-to-target approach. Another challenge is the question of how long therapy should be continued once the treatment target, which should be remission or at least a state of low disease activity, has been reached. The data available suggest that, in most patients with established disease, cessation of biologic therapy will be followed by disease flares, whereas a reduction of dose or an increase in the interval between doses enables maintenance of treatment success. Induction therapy very early in the disease course followed by withdrawal of the biologic agent might also be a feasible approach to attain sustained good outcomes, but currently available data are not strong enough to allow for such a conclusion to be reached. Taken together, this underscores the importance of research into the cause(s) of RA so that curative therapies can be developed.
The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy in patients with active rheumatoid arthritis in the phase 3 MONARCH study, including subpopulations
- G R Burmester
- Y Lin
- E K Mangan
Burmester GR, Lin Y, Mangan EK et al. Efficacy and
safety of sarilumab monotherapy versus adalimumab
monotherapy in patients with active rheumatoid arthritis
in the phase 3 MONARCH study, including
subpopulations. Ann Rheum Dis 2017;76:840-7.
Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a Phase III study
- MC Genovese
- R Fleischmann
- AJ Kivitz
Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial
- JT Giles
- N Sattar
- S Gabriel
Effects of tocilizumab on neutrophil function and kinetics
- LSC Lok
- N Farahi
- JK Juss
Population pharmacodynamic model of neutrophil margination and tolerance to describe effect of sarilumab on absolute neutrophil count in patients with rheumatoid arthritis
- P Kovalenko
- A Paccaly
- A Boyapati
Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi‐database cohort study
- SC Kim
- DH Solomon
- JR Rogers