To Tocilizumab Research Articles

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.

Severe COVID-19 Pneumonia Treated with Tocilizumab in a Pakistani Population: Variables Impacting Outcomes

Background: The association of severity of COVID-19 with raised Interleukin-6 (IL-6) levels led to Tocilizumab (TCZ) approval for treatment based on its IL-6 inhibiting mechanism of action. Treatment outcomes reported have been variable, with little data from Pakistan. Objective: To identify demographic, clinical, and laboratory variables impacting outcomes (recovery or death) of patients with severe COVID-19 pneumonia treated with intravenous tocilizumab in a Pakistani hospital setting. Methodology: A single-center, retrospective, descriptive case series was conducted at the National Hospital Postgraduate Training and Medical Centre, Lahore from April to December 2020. Severe COVID-19 pneumonia (oxygen saturation below 90%, chest HRCT severity score more than 15) administered intravenous tocilizumab was included. Not fulfilling the above inclusion criteria. Data was analysed to identify significant differences between expired patients and those discharged after recovery. Results: Forty-nine patients were admitted to intensive care/ high dependency units (ICU/HDU) with severe COVID pneumonia and treated with intravenous tocilizumab during the study period. The mean age was 61 years, with male predominance. Of the 49 patients, 23 expired. In the expired group lactate dehydrogenase (LDH), and neutrophil to lymphocyte ratio (NLR) were significantly higher throughout the admission course, while D-Dimers plus the last available white blood cell (WBC) count, were significantly higher post-TCZ, as was odds of co-infection evidenced by positive blood cultures. Conclusion: Mortality correlated with increased inflammatory markers LDH and NLR ratio. Post TCZ raised D-Dimers may be indicators of fibrin microthrombi and prophylactic anticoagulation with TCZ may benefit such patients. High odds of secondary bacterial infection post-TCZ had a significant negative impact on recovery.

Tocilizumab for Neuromyelitis Optica Spectrum Disorder


 Patients with neuromyelitis optica spectrum disorder treated with tocilizumab may experience decreased risks of relapse or disability progression compared to before treatment, but it is uncertain whether these changes can be entirely attributed to tocilizumab (TCZ) treatment.
 TCZ might be better than azathioprine for patients with neuromyelitis optica spectrum disorder in reducing relapse risk.
 TCZ might improve or have no impact on pain and fatigue measures for patients with neuromyelitis optica spectrum disorder.
 Adverse events were common during TCZ treatment, but patients treated with TCZ may experience adverse events at a similar or lower rate to those treated with azathioprine.
 One evidence-based guideline suggests that TCZ can be used as 1 of the second-line drugs to prevent long-term relapse for patients with neuromyelitis optica spectrum disorder who have no response to other immunosuppressants.
 We did not find any studies that compared TCZ to other immunosuppressants or any studies on the cost-effectiveness of TCZ for treating neuromyelitis optica spectrum disorder that met the inclusion criteria for this report.

Glycyrrhizin for treatment of CRS caused by CAR T-cell therapy: A pharmacological perspective.

Chimeric antigen receptor T (CAR T)-cell therapy promises to revolutionize the management of hematologic malignancies and possibly other tumors. However, the main side effect of cytokine release syndrome (CRS) is a great challenge for its clinical application. Currently, treatment of CRS caused by CAR T-cell therapy is limited to tocilizumab (TCZ) and corticosteroids in clinical guidelines. However, the theoretical risks of these two agents may curb clinicians' enthusiasm for their application, and the optimal treatment is still debated. CAR T-cell therapy induced-CRS treatment is a current research focus. Glycyrrhizin, which has diverse pharmacological effects, good tolerance, and affordability, is an ideal therapeutic alternative for CRS. It can also overcome the shortcoming of TCZ and corticosteroids. In this brief article, we discuss the therapeutic potential of glycyrrhizin for treating CRS caused by CAR T-cell therapy from the perspective of its pharmacological action.

Drug-induced liver injury following the use of tocilizumab or sarilumab in patients with coronavirus disease 2019

BackgroundsInterleukin-6 (IL-6) blockers including tocilizumab and sarilumab were approved by the U.S. Food and Drug Administration (FDA) in June 2021 for the treatment of patients with moderate to severe COVID-19. The use of sarilumab or tocilizumab in COVID-19 patients has been related to a reduction in mortality compared to standard care. Recent evidence has emerged concerning drug-induced liver injury (DILI) after sarilumab or tocilizumab applications in COVID-19 patients.AimsThe study aimed to estimate DILI associated with sarilumab or tocilizumab in treating moderate to severe patients infected with SARS-Cov-2.MethodsWe conducted a retrospective pharmacovigilance study by data mining of the FDA’s adverse event reporting systems (FAERS) database from the first quarter of 2004 to the fourth quarter of 2021 in confirmed COVID-19 patients. We analyzed DILI cases associated with tocilizumab or sarilumab in treating COVID-19 patients from the FAERS during this period. Disproportionality analysis and Bayesian analysis of COVID-19 patients were utilized for case analysis, and we also next compared the onset time and fatality rates of DILI following tocilizumab or sarilumab.ResultsA total of 275 cases of TCZ or SAR-related DILI reports were extracted. A total of 192 AEs cases were related to tocilizumab (TCZ), and 83 were related to sarilumab (SAR). In patients treated with TCZ, most were < 75 years old (51.57%), with more male than female (46.35% vs. 13.02%). The correlation between IL-6 receptor antagonists and DILI was stronger in SAR (ROR = 12.94; 95%CI 9.6–17.44) than in TCZ (ROR = 1.33; 95%CI 1.14–1.55). The onset time of DILI was different between TCZ and SAR, and a significant difference was observed in TCZ than SAR (P < 0.0001). A significant difference was observed in the mortality rate of TCZ and SAR (P = 0.0009). DILI associated with COVID-19 patients treated with TCZ appeared to have earlier onset-time (1(0–46) day) VS. SAR (3.5(0–27) day).ConclusionThis study shows strict monitor ought to be paid for TCZ or SAR when used for COVID-19 patients with poor liver function.

Tocilizumab treatment in COVID-19: A prognostic study using propensity score matching.

The potential role of interleukin-6 (IL-6) in coronavirus disease 2019 (COVID-19) pneumonia provides the rationale for investigating IL-6 signaling inhibitors. To evaluate and report treatment responses to tocilizumab (TCZ) in COVID-19 patients and compare mortality outcomes with those of standard care. Patients hospitalized with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, diagnosed with reverse transcription polymerase chain reaction (RT-PCR) between March 2020 and April 2021, were enrolled in this single-center retrospective cohort study. Propensity score matching was performed in order to reduce confounding effects secondary to imbalances in receiving TCZ treatment. A total of 364 patients were included in this study. Two hundred thirty-six patients received standard care, while 128 patients were treated with TCZ in addition to standard care (26 (20.3%) patients received a dose of 400 mg intravenously once, while 102 (79.7%) patients received a total dose of 800 mg intravenously). In the propensity score-matched population, less noninvasive mechanical ventilation (p = 0.041) and mechanical ventilation support (p = 0.015), and fewer deaths (p = 0.008) were observed among the TCZ-treated patients. The multivariate adjusted Cox regression model showed a significantly higher survival rate among TCZ patients compared to controls (hazard ratio (HR): 0.157, 95% confidence interval (95% CI): 0.026-0.951; p = 0.044). The hazard ratio for mortality in the TCZ group was 0.098 (95% CI: 0.030-0.318; p = 0.0001 using log-rank test). This study determined that TCZ treatment in COVID-19 patients was associated with better survival, reduced need for mechanical ventilation and reduced hospital-associated mortality.

Effect of IL6 -174 G/C Gene Polymorphism on Response to Interleukin-6 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis

Objective: The main objective of this study was to evaluate the association of IL6-174 G/C gene polymorphisms and the response to tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (s-JIA).&#x0D; Methods: Sixty patients with s-JIA (37 males and 23 females with median age at onset of 5.2 years) who received TCZ were recruited. Basic demographic, laboratory and clinical data were collected alongside the IL-6 haplotype status. The overall response to treatment with TCZ was assessed according to a number of variables including the extent of disease activity reduction, the achievement of clinically inactive disease, the necessity to switch to another biologic disease modifying anti-rheumatic drug (bDMARD) and the achievement of a glucocorticoid-free state.&#x0D; Results: Three IL6 -174 genotypes, including, GG, GC, and CC were found with higher frequencies of GC genotype. These genotypes had non-significant association with the response of s-JIA patients to IL-6 blockade in this cohort study. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response.&#x0D; Conclusion: We observed no significant impact of IL6 -174 G/C gene polymorphisms on treatment response to TCZ in s-JIA Egyptian patients. The observation that a shorted timeframe between symptom onset and diagnosis is associated with better long-term response to TCZ provides evidence for a therapeutic “window of opportunity” in patients with s-JIA.

Common points of therapeutic intervention in COVID-19 and in allogeneic hematopoietic stem cell transplantation associated severe cytokine release syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) and coronavirus disease 2019 (COVID-19) infection can both lead to severe cytokine release syndrome (sCRS) resulting in critical illness and death. In this single institution, preliminary comparative case-series study we compared clinical and laboratory co-variates as well as response to tocilizumab (TCZ)-based therapy of 15 allogeneic-HSCT- and 17 COVID-19-associated sCRS patients. Reaction to a TCZ plus posttransplant cyclophosphamide (PTCY) consolidation therapy in the allogeneic-HSCT-associated sCRS group yielded significantly inferior long-term outcome as compared to TCZ-based therapy in the COVID-19-associated group (P = 0.003). We report that a TCZ followed by consolidation therapy with a Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor given to 4 out of 8 critically ill COVID-19 patients resulted in their complete recovery. Non-selective JAK/STAT inhibitors influencing the action of several cytokines exhibit a broader effect than TCZ alone in calming down sCRS. Serum levels of cytokines and chemokines show similar changes in allogeneic-HSCT- and COVID-19-associated sCRS with marked elevation of interleukin-6 (IL-6), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1) and interferon γ-induced protein 10 kDa (IP-10) levels. In addition, levels of IL-5, IL-10, IL-15 were also elevated in allogeneic-HSCT-associated sCRS. Our multi-cytokine expression data indicate that the pathophysiology of allogeneic-HSCT and COVID-19-associated sCRS are similar therefore the same clinical grading system and TCZ-based treatment approaches can be applied. TCZ with JAK/STAT inhibitor consolidation therapy might be highly effective in COVID-19 sCRS patients.

Durability of Response to Tocilizumab Therapy in Rheumatoid Arthritis: Data from the US-Based Corrona Rheumatoid Arthritis Registry.

IntroductionUnderstanding the durability of response to treatment and factors associated with failure to maintain response in a real-world setting can inform treatment decisions for patients with rheumatoid arthritis (RA). The aim of this study was to analyze durability of response to tocilizumab (TCZ) and factors associated with durability among US patients with RA in routine clinical practice. MethodsTCZ initiators in the Corrona RA Registry were included. Durability of response was defined as maintaining continuous TCZ treatment and either an improvement of at least minimum clinically important difference (MCID) in Clinical Disease Activity Index (CDAI) score or low disease activity (LDA). Secondary analyses included patients treated with intravenous (IV) TCZ and excluded those who discontinued TCZ without reporting reasons for discontinuation. Durability was calculated with Kaplan–Meier survival analysis. Cox proportional hazards modeling identified factors associated with durability.ResultsAmong 1789 TCZ initiators, 466, 272, and 162 were persistent (with or without durable response) with follow-up visits at 1, 2, and 3 years, respectively. Median MCID durability of response in CDAI was > 50% after 36 months overall, 26 months for TCZ-IV, and > 50% after 36 months for those with known reasons for discontinuation; longer durability was associated with increased duration of RA and higher baseline CDAI score and shorter durability with history of malignancy and history of diabetes. Median LDA durability of response was 13.0 months overall, for TCZ-IV, and for those with known reasons for discontinuation; shorter durability was associated with history of malignancy, history of diabetes, and higher baseline CDAI score.ConclusionsMedian durability of response to TCZ in RA was > 3 years when defined as maintenance of MCID in CDAI score and > 1 year with the more stringent criteria of maintenance of LDA.Trial RegistrationClinicalTrials.gov identifier, NCT01402661

An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis.

The present study aimed at evaluating the efficacy of abatacept (ABA) compared to tocilizumab (TCZ), assumed as a gold standard biologic treatment in the management of patients with giant cell arteritis (GCA). Thirty-three biospy-proven GCA consecutive patients were prospectively collected. Odd patients (from 1 to 33) were assigned to TCZ, given either intravenously (IV 8 mg/kg/month), #8 cases, or subcutaneously (SC 162 mg/week) #9, based on patient's preference. ABA was administered subcutaneously at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biological therapies were prescribed in addition to oral prednisone. A single biologic agent was administered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC and 16 ABA). Five patients (15%) needed a therapeutic switch (one patient from TCZ to ABA, and 4 patients from ABA to TCZ). Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial response). Among the TCZ SC group, 7 experienced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance. Both TCZ and ABA can be proposed as an effective therapeutic option in GCA with relevant inflammatory symptoms. ABA can be considered in the patient with absolute or relative or contraindications to TCZ.

Response to interleukin-6 receptor antagonists in patients with rheumatoid arthritis is independent of the number of prior used TNF inhibitors: A systematic review and metaanalysis

To investigate whether early response to tocilizumab (TCZ) and sarilumab (SAR) therapy in patients with active rheumatoid arthritis (RA) is influenced by previous use of biologic agents. We performed a systematic literature review and a meta-analysis of original studies that analyzed the effectiveness of TCZ or SRL in subgroups of RA patients, including biologic-naïve patients versus those with inadequate response to at least one biologic DMARD (bDMARD), and patients with failure to 1 versus≥2 bDMARDs. The study selection process finally included 17 articles corresponding to 14 studies, including 7 randomized controlled trials (RCTs). Although the existing literature that compared the response in biologic-naïve patients versus those with inadequate response to at least one bDMARD showed conflicting results, meta-analysis of 6 published studies revealed a significantly higher likelihood of remission (RR=1.3; 95% CI: 1.2-1.5) and low activity disease (RR=1.3; 95% CI: 1.2-1.4) in the biologic-naïve group at week 24. However, differences between groups were not clinically meaningful in all studies and not always maintained after 6 to 12months of treatment. In addition, data from RCT RADIATE and TARGET suggest that the response to IL-6 pathway inhibitors seems to be similar, regardless of the number of tumor necrosis factor inhibitors (TNFis) previously tested. Disease activity was more rapidly reduced in the early stages of treatment in biologic-naïve patients. However, near similar efficacy can be expected in patients who experienced a failure of at least one bDMARD (mainly TNFis) beyond the first 6 to 12months of treatment, suggesting that the response occurs independently of the number of prior TNFis.

Persistencia a largo plazo de agentes biológicos en el tratamiento de pacientes con Artritis Reumatoidea: una revisión sistemática de la literatura

Treatment persistence is a surrogate marker for long-term treatment success. Objective: To assess the persistence of the biological agents used for treatment of patients with rheumatoid arthritis (RA) over 5 years period and to determine the main causes associated with persistence or discontinuation. Material and methods: A systematic literature review (SLR) was carried out, according to PRISMA recommendations, including Pubmed, Cochrane and Lilacs databases, and studies presented at the ACR, EULAR, PANLAR congresses (2018/2019) until January 2020. Two independent reviewers evaluated the identified publications, by title and abstract and full text, according to PICO methodology. Eligibility criteria were: studies including RA patients ≥ 18 years, treated with biological agents, which measured persistence/ discontinuation for a period of time equal to or greater than 5 years and who were in English or Spanish language. In the case of lack of agreement between the two reviewers, a third reviewer was consulted. The extracted information was analyzed using descriptive statistics, an average percentage of persistence for each biological agent at 5 years was calculated. Results: 56 articles were selected after removal of duplicates and exclusion by title/abs-tract, and by full text. Long-term extension phase of randomized controlled studies were 13, another 15 retrospective cohorts, 18 prospective cohorts and 10 retro-prospective cohorts and corresponded to a total of 72177 (range: 79-10396) patients with RA, with a mean age of 53.8 years ± 12.1, 78.2% female and an average RA disease duration of 9.7 years ± 8.4. In 33.9% of the studies, biological therapy was combined with conventional disease modifying anti-rheumatic drugs (c-DMARDs), in 3.6% monotherapy, 48.2% both modalities, and in 14.3% not reported. One study was in the 1st line (methotrexate näive), 29 studies in 2nd line (inadequate response to MTX and/or c-DMARDs), 5 in 3rd line (inadequate response to biological b-DMARDs), 12 in ≥2nd therapeutic line and in 9 studies did not specify this condition. In 30 studies which evaluated the 2nd therapeutic line, the highest persistence corresponded to tocilizumab (TCZ) 66.41% (95% CI 57.8-79.94), abatacept (ABA) 57.91% (95% CI 50.96-64.87) and golimumab (GOL) 54.38% (95% CI 48.58-60.19). In 10 studies, in which b-DMARD had been analyzed in 3rd therapeutic line, highest retention rates corresponded to rituximab (RTX) 61.19% (95% CI 57.53-66.22) and TCZ 61.1% (95% CI 58.81-63.32). Among studies that evaluated predictors, the most frequently associated with higher survival were: combined treatment with c-DMARD, etanercept versus infliximab and adalimumab and 2nd line of treatment vs. 3rd or 4th line whereas those associated with lower survival rates were: greater use of steroids, higher baseline disease activity, and female gender. Conclusions: In this SLR, the 5-year persistence of b-DMARD in patients with inadequa-te response to DMARs-c and DMARs-b was numerically greater for non-TNFi agents. And among TNFi, GOL presented a higher retention in 2nd therapeutic line.

FRI0220 EFFICACY OF ADJUNCTIVE METHOTREXATE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB PLUS PREDNISONE TAPERING: SUBANALYSIS OF THE GIACTA TRIAL

Background:There is conflicting evidence regarding the efficacy of methotrexate (MTX) in giant cell arteritis (GCA).1,2The benefit of adjunctive treatment with MTX remains to be determined in these patients. Data are presented from a subanalysis of the 52-week, double-blind, randomized controlled GiACTA trial in a subgroup of patients with GCA who received MTX in addition to tocilizumab (TCZ) or placebo (PBO) in combination with prednisone tapering.Objectives:Assess the efficacy of adjunctive MTX in patients with GCA.Methods:In part 1 of GiACTA, patients were randomly assigned to TCZ administered subcutaneously every week (QW) or every other week (Q2W) plus 26-week prednisone tapering or PBO plus 26-week (PBO+26) or 52-week (PBO+52) prednisone tapering.3MTX could be initiated at a stable dose during screening, continued during the double-blind period, and reduced or discontinued at the investigator’s discretion according to disease status. Efficacy was determined as the achievement of sustained remission (absence of GCA flare and C-reactive protein &lt;1 mg/dL from weeks 12 to 52 and adherence to the prednisone taper).3Results:During part 1 of GiACTA, 28 of 250 (11%) treated patients received adjunctive MTX for a median duration of 52.1 weeks: 14 of 149 (9%) TCZ-treated patients received MTX for a median of 52.1 weeks, and 14 of 101 (14%) PBO-treated patients received MTX for a median of 51.9 weeks. Baseline characteristics (Table 1) were balanced between patients who received and did not receive MTX, except for longer disease duration and a higher proportion of patients with relapsing GCA among those who received MTX. The MTX-treated patients tended to have lower prednisone doses at baseline. The median cumulative glucocorticoid dose received over 52 weeks was similar between PBO-treated patients who received MTX and those who did not (3033 mg and 3672 mg, respectively) and between TCZ-treated patients who received MTX and those who did not (1339 mg and 1862 mg, respectively). Sustained remission was achieved by 6 of 14 (43%) patients treated with TCZ + MTX and by 76 of 135 (56%) patients treated with TCZ without MTX (Figure 1). None of the 14 PBO + MTX-treated patients achieved sustained remission, whereas 16 of 87 (18%) patients who received PBO without MTX achieved sustained remission (among all patients in the primary analysis,382 of 149 [55%] in the TCZ groups and 16 of 101 [16%] in the PBO groups achieved sustained remission). The mean annualized relapse rate at 52 weeks was not different between the MTX-treated and MTX-untreated groups for the TCZ (0.76 with MTX vs 0.47 without MTX;p= 0.2549) or PBO (1.89 vs 1.46;p= 0.4611) groups (pvalues based onttests). Rates of adverse events per 100 patient-years were numerically higher in MTX-treated than MTX-untreated patients: 1267 and 858, respectively, in the TCZ groups and 1331 and 952, respectively, in the PBO groups.Conclusion:Preliminary data from a small subgroup of patients suggest that adjunctive MTX does not increase the likelihood of sustained remission, reduce disease relapse rate, or improve steroid sparing in patients with GCA. Response rates in TCZ-treated patients appear to be independent of treatment with MTX. The results from this post hoc analysis in a small sample of GCA patients treated with MTX should be confirmed in larger studies.

In Silico Models Accurately Predict In Vivo Response for IL6 Blockade in Head and Neck Cancer.

Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies. SIGNIFICANCE: A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.

Methotrexate Discontinuation and Dose Decreases After Therapy With Tocilizumab: Results From the Corrona Rheumatoid Arthritis Registry.

IntroductionSimilar outcomes have been observed between patients with rheumatoid arthritis (RA) responding to tocilizumab (TCZ) with methotrexate (MTX) who discontinued vs. continued MTX and between patients receiving MTX who added TCZ vs. switched to TCZ monotherapy. This study examined MTX discontinuation and dose decreases in patients with RA initiating TCZ in a real-world setting.MethodsTCZ-naïve patients enrolled in the Corrona RA registry who initiated TCZ in combination with MTX and had a 6-month follow-up visit without TCZ discontinuation were included. Patients were grouped by MTX dose at the time of TCZ initiation (≤ 10 mg, > 10 to ≤ 15 mg, > 15 to ≤ 20 mg, > 20 mg). The primary outcome was the proportion of patients with changes in MTX use at 6 months, with a secondary analysis at 12 months. Changes in disease activity [Clinical Disease Activity Index (CDAI)] and patient-reported outcomes (PROs) at 6 and 12 months were summarized descriptively.ResultsOf 444 included patients, 82.7% were female and 83.7% white, with mean (SD) disease duration of 11.6 (9.3) years, baseline CDAI score of 24.0 (15.4), and baseline MTX dose of 17.7 (5.8) mg. At 6 months, 139 patients (31.3%) discontinued or decreased their MTX dose. All MTX dose groups and patients who discontinued, decreased, maintained, or increased their MTX dose displayed improvements in CDAI scores and PROs at 6 months. Similar patterns and results were observed at 12 months.ConclusionsA considerable proportion of patients initiating TCZ discontinued or decreased their MTX dose after TCZ initiation. Improvements in disease activity and functionality were observed in patients who decreased or stopped MTX. This real-world study confirmed prior observations that discontinuing or decreasing MTX may be a treatment strategy for patients initiating TCZ combination therapy.Trial RegistrationClinicalTrials.gov identifier, NCT01402661.

Body Mass Index and Clinical Response to Tocilizumab in Patients With Rheumatoid Arthritis.

This study aims to determine whether baseline body mass index (BMI) affects clinical response to tocilizumab (TCZ) after six months of treatment in rheumatoid arthritis (RA) patients. In this prospective study, a total of 52 RA patients (10 males, 42 females; mean age 50.6±12.2 years; range, 23 to 73 years) receiving intravenous TCZ were consecutively recruited and followed-up for six months. BMI was calculated before initiation of TCZ treatment. The primary clinical response criterion was clinical disease activity index (CDAI) low disease activity (LDA) and the secondary clinical response criteria included CDAI remission, disease activity score based on 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) LDA, DAS28-ESR remission, European League Against Rheumatism (EULAR) good response, and decreased DAS28-ESR (ΔDAS28-ESR)≥1.2. The number of RA patients classified as normal weight, overweight, and obese according to baseline BMI was 38 (73.1%), eight (15.4%), and six (11.5%), respectively. Similar baseline BMI median levels were found between RA patients reaching CDAI LDA and non-LDA: 21.11 (18.94-23.72) versus 20.78 (20.03-22.29) (p=0.98), and non-significant difference in the proportion of responders between normal weight and overweight/obese RA patients was found (p=0.47). No significant difference was found when the secondary clinical response criteria were applied. Our study demonstrates that BMI is not associated with clinical response to TCZ among RA patients and TCZ may be used to treat RA patients regardless of BMI levels.

Comparative evaluation of the effects of synthetic disease-modifying antirheumatic drugs and biological agents on clinical course, the rate of development of destructive changes, and quality of life in patients with rheumatoid arthritis

There are few studies of the efficiency of therapy with disease-modifying antirheumatic drugs (DMARDs) and biological agents (BAs) in patients with early rheumatoid arthritis (eRA) as part of a treat-to-target strategy. Objective : to investigate the effects of DMARDs and BAs used in combination with methotrexate (MTX) on clinical course, quality of life (QoL), and the evolution of articular erosions and synovitis in patients with RA. Patients and methods . The investigation enrolled 151 patients with eRA. At the first stage, the patients received DMARDs. At the second stage, 101 patients with persistent moderate and high disease activity were prescribed MTX at a dose of 25 mg/week or 20 mg/week in combination with infliximab (INF), or 20 mg/week in combination with rituximab (RTX). At the third stage, 20patients with persistent high disease activity were switched to tocilizumab (TCZ) therapy. Results and discussion . At 12 months of DMARD therapy, a clinical remission was more often achieved in the MTX group. The use of INF or RTX significantly improved QoL in the patients. That of TCZ as a second- and third-line drug led to a significant decrease in DAS28-CRP. Conclusion . There were no statistically significant differences between the INF and RTMgroups with respect to the time course of changes in CRP, ESR, circulating immune complexes, and the indicators of X-ray progression, which confirms the possibility of switching from a first-line BA to its subsequent lines with an increasing clinical disease activity. TCZ can be a second- and third-line drug when the effect of therapy with other BAs escapes.

The add-on effectiveness and safety of iguratimod in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab

Objectives: To evaluate the effectiveness of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA) who showed an inadequate response to tocilizumab (TCZ), especially patients who were intolerant of an effective dose of methotrexate (MTX).Methods: Thirty-one patients with RA (22 women, age 62.4 years, disease duration 13.8 years, prior TCZ duration 35.7 months, 25 intravenous [8 mg/kg/4 weeks] and 6 subcutaneous [162 mg/2 weeks] TCZ treatments, concomitant MTX 8.5 mg/week [35.5%], and prednisolone (PSL) 4.3 mg/day [25.8%]) who showed an inadequate response to TCZ (disease activity score assessing 28 joints with C-reactive protein [DAS28-CRP] 2.9, clinical disease activity index [CDAI] 15.0, 28 secondary inadequate responders) were treated with additional IGU (final dose 41.7 mg/day) and enrolled in this 24-week, multicenter, retrospective study.Results: Twenty-nine patients (93.5%) continued the treatment for 24 weeks (one dropped out for pneumonia and one for digestive symptoms). The TCZ and the concomitant dose and rate of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (MTX, salazosulfapyridine [SASP], and tacrolimus [TAC]) were not significantly changed during this period. Outcome measures improved significantly, as follows: DAS28-CRP from 2.9 to 1.7 (p < .001); CDAI from 15.0 to 6.0 (p < .001); modified Health Assessment Questionnaire (mHAQ) from 0.8 to 0.6 (p < .05); and rheumatoid factor (RF) from 382.1 to 240.3 IU/mL (p < .001). Using the EULAR criteria, 64.5% achieved a moderate response, and 51.6% achieved ACR 20 at 24 weeks.Conclusion: Adding IGU to inadequate responders to TCZ may be a promising and safe complementary treatment option.

Risk factors for hypersensitivity reactions to tocilizumab introduction in systemic juvenile idiopathic arthritis

Objectives: The objective of this study is to identify risk factors for hypersensitivity reaction (HSR) to tocilizumab (TCZ) in systemic juvenile idiopathic arthritis (sJIA).Methods: Clinical records of 40 patients with sJIA administered TCZ at one center were retrospectively reviewed. Patients were divided into HSR or non-HSR groups depending on the presence of HSR between the first and third TCZ administrations; clinical and laboratory assessments, including serum cytokine profile, were compared.Results: Five patients displayed HSR following the third TCZ administration. They were significantly younger, shorter, and lighter, with a higher peak body temperature than non-HSR patients following the third administration. Their serum C-reactive protein (CRP) level was undetectable following the first administration but detectable by the third administration. Before the third administration, the white blood cell counts and serum levels of CRP and sTNFRII were significantly higher in the HSR group than in the non-HSR group. The serum levels of interleukin-18 and -6 before the third TCZ administration were higher and lower than those before the first administration in the HSR and non-HSR groups, respectively.Conclusion: Patients with sJIA having a younger age, shorter stature, and lighter weight and those showing increased disease activity in the early period of TCZ administration may be at higher risk of TCZ-induced HSR.

Tocilizumab treatment leads to improvement in disease activity regardless of CCP status in rheumatoid arthritis.

Autoantibodies can be useful in predicting response to certain treatments in rheumatoid arthritis (RA). We aimed to evaluate initial response to tocilizumab (TCZ) by change in physician and patient-reported outcomes and laboratory parameters in a real-world cohort of patients with RA. We analyzed the data by autoantibody status to determine whether patients with seronegative RA had improved response to tocilizumab when compared to their seropositive counterparts. Data from the CORRONA RA registry were analyzed. Patients were included if they were started on TCZ and had data from a follow-up visit 4-8 months after initiation, as well as having information on serologic status. Serologic status was determined by presence of anti-cyclic citrullinated peptide (CCP) antibodies. Changes in disease activity measures from baseline to follow-up visit were evaluated. Both CCP-negative and -positive groups had statistically significant improvement in physician-reported measurements (physician rating of disease activity and joint counts), patient-reported measures (disease activity, pain, and fatigue), and acute phase reactants after 4-8 months of treatment with tocilizumab. The magnitude of improvement, however, did not differ significantly by CCP status. Tocilizumab led to statistically significant improvement in all patient- and physician-reported measures of disease activity evaluated in this cohort of patient with RA. The response to tocilizumab did not differ by CCP status.