Tocilizumab In Rheumatoid Arthritis Patients Research Articles

Interleukin-6: Cardiovascular Aspects of Long-Term Cytokine Suppression in Patients with Rheumatoid Arthritis.

In recent years, many atherogenesis researchers have focused on the role of inflammatory cytokines in the development of cardiovascular disease (CVD). Interleukin-6 (IL-6) cytokine is independently associated with higher CVD risk in patients with rheumatoid arthritis (RA). The effect of IL-6 inhibitors on the cardiovascular system in RA patients remains poorly understood, especially with its long-term use. This study investigates the effect of therapy with IL-6 receptor blocker tocilizumab (TCZ) on the dynamics of cardiovascular risk (CVR), modifiable risk factors (RFs), carotid artery (CA) structural changes, and the incidence of cardiovascular complications (CVCs) in RA patients during a 265-week follow-up period. Forty-five patients with active RA (DAS28-ESR 6.2 (5.5;6.8) with ineffectiveness and/or intolerance to disease-modifying antirheumatic drugs (DMARDs) were included in this study. During long-term therapy with TCZ in RA patients, no increase in CVR and no significant structural changes in CA were observed. No significant changes in the blood lipid spectrum were observed in patients without statin therapy. In the group of patients receiving statins, there was a 43% increase in high-density lipoprotein cholesterol (HDL-C), a 15% reduction in total cholesterol levels, and a 56% decrease in the atherogenicity index (p < 0.01 in all cases). Associations were found between ∆ total cholesterol and ∆ C-reactive protein (CRP) (R = 0.36, p = 0.04), ∆ low-density lipoprotein cholesterol (LDL-C), and ∆-CRP (R = 0.42, p = 0.03) in RA patients receiving statins. Initially, the thickness of the intima-media complex of carotid arteries (cIMT) positively moderately correlated with age (R = 0.7; p < 0.01), BMI (R = 0.37; p < 0.01), and systolic blood pressure (R = 0.64; p < 0.01); however, it weakly correlated with the lipid spectrum parameters: total cholesterol (R = 0.29; p < 0.01) and LDL-C (R = 0.33; p < 0.01). No new associations of cIMT by the end of the follow-up period, as well as the relationship of cIMT value with RA activity and therapy, were revealed. Patients with carotid ASPs showed an oppositely directed relationship between total cholesterol and sVCAM-1 at baseline (R = -0.25, p = 0.01) and at the end of this study (R = 0.29, p < 0.01). The incidence of cardiovascular events was 0.53 per 100 patient-years during the 265-week period of TCZ therapy.

Serum GM-CSF level is a predictor of treatment response to tocilizumab in rheumatoid arthritis patients: a prospective observational cohort study

BackgroundThe aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF).MethodsActive adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on.ResultsDisease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups.ConclusionThe high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.

A multi-biomarker panel for predicting Tocilizumab response in Rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation in the synovial lining of the joints. Key inflammatory cytokines such as interleukin-6 (IL-6), TNF-α, and others play a critical role in the activation of local synovial leukocytes and the induction of chronic inflammation. Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, has demonstrated significant clinical efficacy in treating RA patients. However, similar to other inflammatory cytokine blockers, such as TNF-alpha inhibitors, Interleukin-1 inhibitors, or CD20 inhibitors, some patients do not respond to treatment. To address this challenge, our study employed a high-precision proteomics approach to identify protein biomarkers capable of predicting clinical responses to Tocilizumab in RA patients. Through the use of data-independent acquisition (DIA) mass spectrometry, we analyzed serum samples from both TCZ responders and non-responders to discover potential biomarker candidates. These candidates were subsequently validated using individual serum samples from two independent cohorts: a training set (N = 70) and a test set (N = 18), allowing for the development of a robust multi-biomarker panel. The constructed multi-biomarker panel demonstrated an average discriminative power of 86 % between response and non-response groups, with a high area under the curve (AUC) value of 0.84. Additionally, the panel exhibited 100 % sensitivity and 60 % specificity. Collectively, our multi-biomarker panel holds promise as a diagnostic tool to predict non-responders to TCZ treatment in RA patients.

Short-Term Efficacy and Safety of Subcutaneous Tocilizumab in Rheumatoid Arthritis Patients in Pakistan: A Real-World Experience

Objective: To determine the real-world efficacy and safety of subcutaneous Tocilizumab in patients with rheumatoid arthritis.&#x0D; Study Design: Case series.&#x0D; Place and Duration of Study: Department of Rheumatology, National Hospital and Medical Centre, Lahore Pakistan, from Aug 2019 to Dec 2020.&#x0D; Methodology: In this study, 33 patients receiving subcutaneous Tocilizumab 162 mg every two weeks as monotherapy or with conventional synthetic disease modifying anti-rheumatic drugs were followed per standard study protocol. Increasing or decreasing the dosing interval was allowed according to disease activity at the discretion of the treating rheumatologist. The primary outcome was patients achieving Low Disease Activity as per Clinical Disease Activity Index (&gt;2.8-10.0) and Disease Activity Score-28(&gt;2.6-3.2). The secondary outcome was a clinically meaningful improvement in Disease Activity Score -28 (reduction of ≥1.2 units in Disease Activity Score-28 score). Adverse events were recorded at each follow-up visit.&#x0D; Results: Of the 33 patients, 25(75.8%) were biologics-naive, 9(27.2%) patients achieved the target of Low Disease Activity as per Clinical Disease Activity Index (2.9-10.0) and 8(24.2%) patients achieved Low Disease Activity as per Disease Activity Score-28(2.7-3.2). At six months, the proportion of patients achieving clinically meaningful improvement (decrease ≥1.2) in Disease Activity Score -28 was 13(54.2%). Overall, 14(42.4%) patients developed adverse events and 3(9.1%) patients discontinued Tocilizumab owing to adverse events.&#x0D; Conclusion: Tocilizumab has been seen to be an effective biologic in only one-third of patients, and it was tolerated in twothirds of the patients.Keywords: Conventional synthetic disease modifying anti-rheumatic drugs, Efficacy, Rheumatoid arthritis, Safety, Subcutaneous tocilizumab.

LC-MS/MS method for the quantitation of serum tocilizumab in rheumatoid arthritis patients using rapid tryptic digestion without IgG purification

The quantitation of serum tocilizumab using liquid chromatography tandem-mass spectrometry (LC-MS/MS) method has not been widely applied in clinical settings because of its time-consuming and costly sample pretreatments. The present study aimed to develop a validated LC-MS/MS method for detecting serum tocilizumab by utilizing immobilized trypsin without an immunoglobulin G purification step and evaluate its applicability in the treatment of rheumatoid arthritis (RA) patients administered intravenously or subcutaneously with tocilizumab. The tocilizumab-derived signature peptide was deciphered using a nano-LC system coupled to a hybrid quadrupole-orbitrap mass spectrometer. The serum tocilizumab was rapidly digested by immobilized trypsin for 30 min. The chromatographic peak of the signature peptide and that of the internal standard were separated from the serum digests for a total run time of 15 min. The calibration curve of serum tocilizumab concentration was linear with a range of 2–200 μg/mL. The intra- and inter-day accuracy and relative standard deviation (RSD) were 90.7%–109.4% and <10%, respectively. The serum tocilizumab concentrations in the RA patients receiving intravenous and subcutaneous injections were 5.8–28.9 and 2.4–63.5 μg/mL, respectively. The serum tocilizumab concentrations using the current method positively correlated with those using the enzyme-linked immunosorbent assay, although a systematic error was observed between these methods. In conclusion, a validated LC-MS/MS method with minimal sample pretreatments for monitoring serum tocilizumab concentrations in RA patients was developed.

Associations between the interleukin-6 rs1800795 G/C and interleukin-6 receptor rs12083537 A/G polymorphisms and response to disease-modifying antirheumatic drugs in rheumatoid arthritis: A meta-analysis

ObjectiveWe aimed to investigate the association between interleukin-6 (IL-6) rs1800795 G/C, IL-6 receptor (IL-6R) rs12083537 A/G, and rs4329505 T/C polymorphisms and responsiveness to disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). MethodsWe searched Medline, Embase, and Web of Science databases. We conducted a meta-analysis of studies on the association between the IL-6 rs1800795 G/C, IL-6R rs12083537 A/G and rs4329505 T/C polymorphisms and responsiveness to DMARDs in RA patients. ResultsFourteen studies from eight published articles involving 982 patients were included in this meta-analysis. The meta-analysis showed a significant association between the IL-6 rs1800795 G allele and response to DMARDs in RA (P = 0.008). Stratification by DMARD class showed that the IL-6 rs1800795 G allele was significantly associated with responsiveness to biological DMARDs (bDMARDs) (P = 0.022), but not conventional synthetic DMARDs (P = 0.145). A significant association was also found between the IL-6 rs1800795 G/C polymorphism and response to DMARDs. The meta-analysis revealed a significant association between the IL-6R rs12083537 A allele and response to tocilizumab in RA patients (P = 0.001). A significant association was also found between the IL-6R rs12083537 AA genotype and response to tocilizumab in RA patients (P = 0.001). However, no association was found between the IL-6R rs4329505 T/C polymorphism and response to tocilizumab. ConclusionsThis meta-analysis revealed associations between treatment response to bDMARDs and the IL-6 rs1800795 G/C polymorphism, and between response to tocilizumab and the IL-6R rs12083537 A/G polymorphism in RA.

Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Background Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells). Design The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor. Participants Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population. Main outcome measures The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of &lt; 10.1, defined for simplicity as CDAI major treatment response (CDAI-MTR). Secondary outcomes included the assessment of CDAI response in the B-cell-rich cohort, in which the non-inferiority of rituximab compared with tocilizumab was evaluated. Safety data up to week 48 are reported. Results In total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population (n = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group. Conclusion To our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility. Trial registration Current Controlled Trials ISRCTN97443826. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 7. See the NIHR Journals Library website for further project information.

Differences in the strength of inhibition of interleukin-6 signalling by subcutaneous sarilumab and tocilizumab in rheumatoid arthritis patients.

To assess differences in the strength of inhibition of IL-6/STAT3 signalling induced by subcutaneously (sc) administered tocilizumab (TCZ) and sarilumab (SAR). Data were collected on patients with rheumatoid arthritis (RA) who achieved low disease activity (Clinical Disease Activity Index [CDAI]≤10) following treatment with weekly or bi-weekly administration of 162 mg sc of TCZ (TCZ qw group, n=8; TCZ q2w group, n=8), bi-weekly doses of 200 mg sc of SAR (SAR q2w group, n=7), or MTX (n=8) as a control. The clinical characteristics of each group were collected, and the serum concentrations of IL-6 and soluble IL-6 receptor (sIL-6R) were measured using ELISA. Whole blood samples from each group were stimulated with 100 ng/ml of IL-6. The proportion of phosphorylated (p)STAT3-positive CD4+ T cells was measured using phosflow cytometric analysis. The proportion of pSTAT3-positive CD4+ T cells following stimulation with 100 ng/ml of recombinant human IL-6 was significantly different among the groups (median 1.8% [0.9-3.0] vs. 7.7% [2.9-8.0] vs. 12.5% [11.4-16.6] vs. 71.5% [68.0-78.5] for the TCZ qw, SAR q2w, TCZ q2w, and MTX control groups, respectively; p<0.01 for all comparisons). SAR 200 mg q2w showed significantly stronger inhibition of IL-6/STAT3 signalling than TCZ sc q2w but weaker inhibition than TCZ sc qw. The results of this study may be useful for adjusting the IL-6 blockade treatment for patients with RA.

Doppler ultrasound impacts response to intravenous tocilizumab in rheumatoid arthritis patients.

Within rheumatoid arthritis (RA) patients treated with intravenous tocilizumab (IV-TCZ), it is unclear if power Doppler ultrasonography (PDUS) can predict future clinical response. This study sought to determine if baseline PDUS or its early changes can predict 12-week and 24-week disease activity outcomes, and quantify the need for dose escalation (4 to 8mg/kg). Fifty-four RA patients starting IV-TCZ were evaluated at baseline, 4, 6, 12, 16, and 24weeks using 34-joint PDUS (US34-PDUS), clinical disease activity index (CDAI), 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR), ACR 20/50/70, health assessment questionnaire-disability index (HAQ-DI), and PDUS 20/50/70, a novel measure. Logistic regression models evaluated the predictive utility of US34-PDUS of DAS28-ESR response after adjusting for covariates. Ninety-four percent of patients required dose escalation to 8mg/kg. US34-PDUS, CDAI, and DAS28-ESR improved significantly over 24weeks (p < 0.001). Baseline PDUS and 12-week PDUS change correlated with CDAI at 24weeks (p < 0.05). Logistic regression demonstrated baseline US34-PDUS was independently associated with DAS28-ESR ≥ 1.2 response, even after adjusting for baseline DAS28-ESR (p = 0.03). CDAI, DAS28-ESR, and their components increased across PDUS 20/50/70 categories; however, HAQ-DI did not. RA patients treated with IV-TCZ for 24weeks demonstrated significant improvement, and baseline/early changes in PDUS were predictive of later clinical response. The PDUS 20/50/70 measure is a novel metric of response. This study suggests that IV-TCZ 4mg/kg may not be sufficient to attain low RA disease activity at 12weeks, in RA patients with moderate to severe disease (DAS28 ≥ 4.4 and US34-PDUS ≥ 10). ClinicalTrials.gov NCT01717859 Key Points • Over 90% of RA patients with baseline DAS28-ESR ≥ 4.4 and PDUS34 ≥ 10 required intravenous tocilizumab dose escalation from 4 to 8mg/kg at 12weeks. • Reduction in power Doppler ultrasonography (US34-PDUS) scores correlate with DAS28-ESR and CDAI over 24weeks in rheumatoid arthritis patients with moderate to severe disease activity. • Baseline US34-PDUS predicts future improvements in clinical disease activity outcomes, independent of baseline DAS28-ESR. • Clinical response measures, DAS28-ESR and CDAI, improved across US34-PDUS 20/50/70 categories, while patient-reported outcomes did not.

Health-economic analysis of tocilizumab in patients with rheumatoid arthritis and systemic juvenile arthritis

Rationale . Rheumatoid arthritis (RA) and systemic juvenile arthritis (sJA) are the most frequent rheumatic diseases in adults and adolescents, consequently. Biologics disease modifying antirheumatic drugs (bDMARDs) are eff ective in treatment of RA and s JA. Aim . To perform health-economic analysis of tocilizumab for subcutaneous and intravenous injections in patients with RA and sJA comparing to TNF-α inhibitors. Materials and methods . Cost-minimizing analysis was used from the perspective of healthcare system (accounting for direct medical costs) with the modelling horizon — 1 year. We included into the model cost of RA and sJA bDMARDs, cost of adverse events correction and costs of laboratory and instrumental diagnostic. Results . Cost minimizing ratio of tocilizumab (subcutaneous form) in RA patients comparing to adalimumab (Humira), сertolizumab pegol, golimumab were 111 536; 129 094; 85 244 RUR, consequently favour to tocilizumab. Tocilizumab was less costly comparing to adalimumab (Humira), certolizumab pegol, golimumab by 12.8, 14.5, 10,0 %, consequently. Cost minimizing ratio of tocilizumab in RA patients comparing to adalimumab (Dalibra), etanercept, infl iximab (Remicade) were 40 497; 54 355; 28 419 RUR in favour to comparators. Tocilizumab was more costly comparing to adalimumab (Dalibra) etanercept, infl iximab (Remicade) by 5.6; 7.7; 3.9 %, consequently. Cost minimizing ratio of tocilizumab in sJA patients comparing to kanakinumab, adalimumab (Humira) and adalimumab (Dalibra) were 6 535 234; 478 297 and 323 263 RUR. Tocilizumab was less costly comparing to kanakinumab, adalimumab (Humira) and adalimumab (Dalibra) by 93.3; 50.6 and 41.1 %, consequently. Conclusions . Tocilizumab is economically reasonable comparing to others TNF-α inhibitors in patients with RA and sJA.

Correlation of fatigue with other disease related and psychosocial factors in patients with rheumatoid arthritis treated with tocilizumab: ACT-AXIS study.

To assess the hypothesis if tocilizumab (TCZ) is effective on disease activity, and also its effect in fatigue and other clinical and psychological disease-related factors in patients with rheumatoid arthritis (RA) treated with TCZ.A 24-week, multicenter, prospective, observational study in patients with moderate to severe RA receiving TCZ after failure or intolerance to disease-modifying antirheumatic drugs or tumor necrosis factor-alpha was conducted.Of the 122 patients included, 85 were evaluable for effectiveness (85% female, 51.9 ± 12.5 years, disease duration 8.7 ± 7.4 years). Mean change in C-reactive protein level from baseline to week 12 was −11.2 ± 4.0 (P < .001). Mean Disease Activity Index score (DAS28) decreased from 5.5 ± 1.0 at baseline to 2.7 ± 1.3 (P < .001) at week 24. Mean change in Functional Assessment of Chronic Illness Therapy score was −5.4 ± 11.2 points at week 24. Multiple regression analysis showed that the improvement in DAS28, sleep, and depression explained 56% and 47% of fatigue variance at week 12 and 24, respectively.Tocilizumab is effective in reducing disease activity and results in a clinically significant improvement in fatigue, pain, swollen joint count, morning stiffness, sleepiness, depression, and DAS28; the last 3 were specifically identified as factors explaining fatigue variance with the use of TCZ in RA patients.

A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.

Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis.

Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8mg every 28days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24weeks of treatment above 100 × 103 μghml-1 . A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104lh-1 , 4.83l, 0.239mgh-1 and 4.22μgml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

Safety of Tocilizumab in Rheumatoid Arthritis Patients with Resolved Hepatitis B Virus Infection: Data from Real-World Experience.

To investigate whether the use of IL-6 receptor antagonist (tocilizumab) might be associated with hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients, particularly in those with resolved HBV infection [HBV surface antigen (HBsAg) negative and antibody to HBV core antigen (anti-HBc) positive, serologically]. HBsAg, anti-HBc, antibody to HBsAg (anti-HBs), and HBV DNA titers were measured in RA patients who had continuously received tocilizumab for more than 3 months. Patients were divided into two groups according to the presence of anti-HBc. Clinical and laboratory data, in addition to medications administered along with tocilizumab during the treatment duration with tocilizumab, were compared between the two groups. HBV reactivation was defined as the presence of HBV DNA in sera, and alterations in HBsAg, anti-HBc, and anti-HBs titers according to the use of tocilizumab were also evaluated. Fifteen of 39 patients (38.5%) had anti-HBc positivity, while 24 patients (61.5%) did not. There were no differences in demographic data, serologic classification, and variables related to tocilizumab between the anti-HBc-positive and -negative groups. Comparison of the medications administered along with tocilizumab treatment revealed no meaningful differences. None of the patients experienced reactivation of HBV. In addition, in 15 patients with resolved HBV infection, no alterations in HBsAg, anti-HBc, and anti-HBs titers were observed with the use of tocilizumab. Tocilizumab may be applied to RA patients safely with few concerns for HBV reactivation, particularly in those with resolved HBV infection.

Efficacy and Rapid Response of Tocilizumab in Rheumatoid Arthritis Patients not Responder to Previous Biologic Therapy

Efficacy and Rapid Response of Tocilizumab in Rheumatoid Arthritis Patients not Responder to Previous Biologic Therapy

Genome-Wide Association Study of Overall and Progression-Free Survival after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (DISCOVeRY-BMT study)

While survival outcomes after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT) have significantly improved over the last 2 decades, about 40% of patients die of various causes before one-year post-URD BMT. We performed a genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of overall (OS) and progression-free (PFS) survival in 3,532 patients treated for AML, ALL or MDS and reported to CIBMTR from 2000-2011 and their 8/8 HLA-matched URDs. Cohort 1 consisted of 2,609 patients with 10/10 HLA-matched URD BMT from 2000-08; Cohort 2 consisted of 923 patients with 10/10 HLA-matched URD BMT from 2009-11 and 8/8 (but <10/10) HLA-matched URD BMT from 2000-11. Genotyping on recipients and donors was performed using the HumanOmniExpress-24 BeadChip (Illumina, San Diego, CA), containing approximately 730,000 single nucleotide polymorphisms (SNPs); the CEU reference panel from the 1000 Genomes project (March 2012 release) was used to impute additional genotypes not available on the GWAS chip or that failed typing. Samples were pre-phased with SHAPEIT and genotypes inferred using IMPUTE2. After quality control, Cohort 1 included 2,108 recipients and 2,052 donors and Cohort 2 included 773 recipients and 760 donors of European-American ancestry typed at 637,655 markers and ~9 million imputed SNPs. Each SNP was measured for association with OS and PFS using Cox proportional hazard models in R. All models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT (early, intermediate, advanced), cell source (blood, marrow) and year of BMT. P-values were combined using METAL software with weights proportional to the square root of the number of cases. We report results for a combined P -value (Pmeta) <5x10-8.The T allele of rs9990017 in recipients is significantly associated with better OS (Table) yielding about a 30% decreased hazard of all causes of death including disease relapse, graft-versus-host disease, infection and organ failure. Analysis of the effect of donor genotype at this SNP shows no evidence of association with OS or PFS. The strongest imputed association in this region (info score >.98) was rs9857765 with the T allele at this locus conferring a significantly improved OS in both cohorts (Table).Two SNPs (rs9845520 and rs9839074) in strong linkage disequilibrium (r2 =.94) with both rs9857765 and rs9990017, are predicted to affect transcription factor binding (Regulomedb score=2b) of the highly-conserved gene MBNL1 and the common allele in rs9839074 is predicted to be in an important position in the GATA1 (erythroid development) motif and a binding site for CEBPB, STAT3 and FOS across multiple cell lines. MBNL1 protein is expressed in most blood and marrow hematopoietic cells, while MBNL1 mRNA is expressed in many organs. CEBPB regulates immune response genes, is required for normal macrophage function/differentiation and can interact with (among others) glucocorticoid receptor, IL-6, TNF-alpha and transporter proteins conferring multi-drug resistance (ABCC2, ABCB1). Normal activation of STAT3 is required for self-renewal of embryonic stem cells and differentiation of TH17 cells, while constitutive activation of STAT3 is associated with poor prognosis in acute leukemia. FOS is involved with CD16+ signaling in NK cells, vitamin D receptor gene regulation in osteoporosis, and proliferation of hematopoietic cells, among other roles.A region on 13q34 showed evidence of association with PFS; recipients whose donor had a T allele at rs11617176 showed improved PFS compared to those whose donors had the C allele (see Table). This region contains variants identified in other GWAS of mean platelet volume, coronary artery disease, interstitial lung disease, response to tocilizumab in rheumatoid arthritis patients and renal transplant outcomes, among others.Our study, DISCOVeRY-BMT, is the first GWAS for URD BMT survival outcomes. Confirmation of these findings in a third cohort, genotyping of imputed SNPs, and further studies of the functional consequences of these SNPs may provide more individualized risk prediction and prognosis, while confirmation of rs11617176 may aid in donor selection. [Display omitted] DisclosuresHahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding. McCarthy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NHLBI: Research Funding.

Potential patient benefit of a subcutaneous formulation of tocilizumab for the treatment of rheumatoid arthritis: a critical review.

Treatment of rheumatoid arthritis (RA) was revolutionized during the last decade with the development of new biologic disease-modifying anti-rheumatic drugs (DMARDs) enabling the targeting of immune cells and cytokines other than tumor necrosis factor (TNF). Subcutaneous formulations of the newer biologic DMARDs facilitate not only patients’ emancipation from the hospital, but reduce both societal and medical costs. Intravenous tocilizumab (TCZ) in RA has an efficacy and safety profile similar to anti-TNF in both the short and long-term. However, TCZ can be administered in monotherapy without loss of efficacy when patients do not tolerate methotrexate or synthetic DMARDs. TCZ is consistently found superior to methotrexate and possibly superior to adalimumab in monotherapy in randomized controlled trials. Subcutaneous administration of TCZ is as effective and safe as its intravenous administration in RA patients during the first year of treatment. Similar to intravenous TCZ, patients’ weight and possibly previous use of anti-TNF influence the efficacy of subcutaneous TCZ. Additionally, combination with synthetic DMARDs seems to expose RA patients to more adverse events independently of its administration route. Pharmacokinetics of different administration routes could potentially lead to differences in efficacy, adverse events, and auto-immunogenicity. The concentration of free TCZ before new TCZ dose (C trough) is higher in the subcutaneous route, while the maximal concentration of free TCZ is higher in the intravenous route. The subcutaneous dosages of TCZ 162 mg every week, and every 2 weeks in RA patients with low body weight (<60 kg) work well. Nevertheless, dosage and intervals of subcutaneous TCZ administration could be adjusted during the course of treatment since 80% of non-Japanese RA patients with usually higher body weight achieved similar efficacy with the low TCZ dosage in combination with a synthetic DMARD. Patients want effective, easy-to-administer therapy with sustained prolonged efficacy without the need of polypharmacy and with minimal to no side effects. Subcutaneous TCZ in RA patients in monotherapy seems to live up to patients’ expectations.

SAT0257 Clinical and Radiographic Effects after 52-Week of Adding Tocilizumab or Switching to Tocilizumab in RA Patients with Inadequate Response to Methotrexate: Results from A Prospective Randomized Controlled Study (Surprise Study)

BackgroundThe SURPRISE study is an open-label trial comparing the strategy of tocilizumab (TCZ) plus methotrexate (MTX) (ADD-ON) with the strategy of switching to TCZ (SWITCH) in Japanese rheumatoid arthritis (RA)...

AB0453 Response to TOCILIZUMAB in Rheumatoid Arthritis is not Influenced by the Body Mass Index of the Patient

ObjectivesTo assess relationship between body mass index (BMI) and efficacy of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients.MethodsWe conducted a retrospective study of the use of TCZ in patients with...

FRI0314 Safety of the Newer Biological Dmards, TOCILIZUMAB and Abatacept, in Rheumatoid Arthritis (RA) Patients with A History of HBV Infection: A REAL Life Experience

BackgroundHBV infection represents a major issue in RA patients undergoing biological disease-modifying anti-rheumatic drugs (bDMARDs) treatment (1). While several studies deal with the risk of hepatitis reactivation under anti-TNF agents,...