Tocilizumab In Combination Research Articles

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm

BackgroundCytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes.Research QuestionDo immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)?Study Design and MethodsWe conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality.ResultsFive thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment.InterpretationThe combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.

Experience of using tocilizumab in the research unit of infectious hospital for patients with coronavirus infection (CoVID-19)

The objective of the study was the evaluation of the effectiveness of tocilizumab in patients with coronavirus infection COVID-19 who were treated in the intensive care unit of an infectious diseases hospital. Material and methods. There was carried out a retrospective analysis of the case histories of 40 patients with confirmed severe and extremely severe coronavirus infection COVID-19. The average age of the patients was 58.3 ± 1.8 years, the total lung lesion volume was 83.2 ± 2.0%. Results: The survival rate of patients who received immunosuppressive therapy with tocilizumab in combination with pulse therapy of glucocorticosteroids was 55%, and 44% of patients with 100% lung involvement. The use of tocilizumab (4-8 mg / kg) led to a statistically significant decrease in the level of C-reactive protein in the blood, which was an indicator of adequate pharmacotherapy of the "cytokine storm" in the ICU.

Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatment in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p < 0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p < 0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.

Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 'Cytokine Storm': A Retrospective Observational Cohort Study

Background: Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. Methods: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020 and April 15, 2020, were included. Cytokine storm was defined by inflammatory markers: ferritin >700ng/mL, C-reactive protein >30mg/dL, or lactate dehydrogenase >300U/L. Patients were subdivided into six groups -no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-interleukin 6 (IL-6) antibody (tocilizumab) or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. Results: There were 3,098 patients who met inclusion criteria. The most common comorbidities were hypertension (40-56%), diabetes (32-43%) and cardiovascular disease (2-15%). Patients most frequently met criteria with high lactate dehydrogenase (74·8%) alone, or in combination, followed by ferritin (71·4%) and C-reactive protein (9·4%). More than 80% of patients had an elevated D-dimer. Patients treated with a combination of tocilizumab and corticosteroids (Hazard Ratio [HR]: 0·459, 95% Confidence Interval [CI]: 0·295-0·714; p<0·0001) or corticosteroids alone (HR: 0·696, 95% CI: 0·512-0·946; p=0·01) had improved hospital survival compared to standard of care. Corticosteroids and tocilizumab was associated with increased survival when compared to corticosteroids and anakinra (HR: 0·612, 95% CI: 0·391-0·958; p-value=0·02). Conclusions: When compared to standard of care, corticosteroid and tocilizumab used in combination, or corticosteroids alone, was associated with reduced hospital mortality for patients with COVID-19 cytokine storm. Funding Statement: A.S.C. was supported by The Primary Immune Deficiency Treatment Consortium (U54 AI 082973), funded jointly by the National Center for Advancing Translational Sciences (NCATS) and the National Institute of Allergy and Infectious Diseases (NIAID). O.B. was supported by grants from the US DOD (#W81XWH-15-1-0614) and the New York State Spinal Cord Injury Research Board (DOH01-ISSCI6- 2016-00018). N.H. was supported by a grant from the Patient Centered Outcomes Research Institute (PCORI # AD-1511-33066). Declaration of Interests: There are no competing interests. Ethics Approval Statement: The Institutional Review Board for the Feinstein Institutes of Medical Research at Northwell Health approved this study as minimal-risk research and waived the requirement for informed consent.

Research in Brief

Gerd Burmester and colleagues randomly assigned 259 patients with rheumatoid arthritis who had achieved remission or low disease activity on a combination of tocilizumab and prednisone to continue prednisone (n=128) for 24 weeks or taper prednisone, reaching 0 mg per day at week 16 (n=131). All patients remained on tocilizumab. The estimated mean change in Disease Activity Score for 28 joints–erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 24 (the primary outcome) was −0·08 (95% CI −0·27 to 0·12) with continued prednisone and 0·54 (0·35 to 0·73) with tapered prednisone (difference 0·61 [0·35 to 0·88] in favour of continued prednisone; p<0·0001). 99 (77%) patients on continued prednisone and 85 (65%) on tapered prednisone were treated successfully (defined as low disease activity, an absence of disease flares, and no confirmed adrenal insufficiency; relative risk 0·83, 95% CI 0·71–0·97). Seven (5%) patients in the tapered prednisone group and four (3%) in the continued prednisone group had at least one serious adverse event.

The Combination of Tocilizumab and Methylprednisolone Along With Initial Lung Recruitment Strategy in Coronavirus Disease 2019 Patients Requiring Mechanical Ventilation: A Series of 21 Consecutive Cases.

Objective:To describe the outcomes with use of a combination of tocilizumab and methylprednisolone administered around the time of endotracheal intubation in patients with confirmed coronavirus disease 2019-associated hypoxemic respiratory failure requiring mechanical ventilation.Data Sources:Retrospective chart review.Study Selection/Data Extraction:Twenty-one consecutive patients with confirmed coronavirus disease 2019-associated hypoxemic respiratory failure requiring mechanical ventilation. Initial ventilator parameters were positive end-expiratory pressure 14 cm H2o and target plateau pressure 29 cm H2o to maximize lung recruitment. Methylprednisolone (125 mg every 6hr for 24 hr with tapering to 60 mg every 12 hr) was administered shortly after patients were intubated (median 11 hr after intubation).Data Synthesis:No patient in the cohort died while hospitalized (mortality, 0%; 95% CI, 0%–18%) and 18 patients have been discharged from the acute care setting. Twenty of 21 patients (95%) have been liberated from mechanical ventilation after a median duration of 8 days (range, 4–30 d). Following 48 hours of methylprednisolone, the A-a o2 gradient decreased from 455 ± 103 to 228 ± 109 mm Hg (difference 227 ± 108 mm Hg; p < 0.01).Conclusions:Our positive experience with tocilizumab in combination with methylprednisolone started early after endotracheal intubation may be one avenue for reducing the morbidity and mortality seen with severe coronavirus disease 2019 and merits further exploration in clinical studies.

Dynamic Contrast-Enhanced MRI Confirms Rapid And Sustained Improvement Of Rheumatoid Arthritis Induced By Tocilizumab Treatment: An Italian Multicentre Study.

ObjectiveThis open-label study evaluated the effects of combined tocilizumab (TCZ) and disease-modifying antirheumatic drugs (DMARDs) on magnetic resonance imaging (MRI) changes in synovial membrane enhancement, bone marrow edema (BME), and erosions in the wrist and hand joints of rheumatoid arthritis (RA) patients inadequately responding to DMARDs alone.MethodsThe efficacy of intravenous TCZ 8 mg/kg administered every four weeks for 48 weeks was evaluated on six occasions. The primary endpoints were the changes in the extent and degree of wrist synovitis as measured using the RA MRI Score (RAMRIS) and dynamic, gadolinium-enhanced 0.2T MRI (DCE-MRI). A number of different parameters of DCE-MRI were evaluated.ResultsFifty-eight patients were treated, eight of whom (13.8%) discontinued the study prematurely. The mean RAMRIS significantly decreased after two weeks and the decrease was maintained for up to 48 weeks. By week 4, the mean RAMRIS synovitis score had significantly decreased from baseline (−0.804±1.575; p=0.018), but not the mean early enhancement (REE) or relative enhancement (RE). However, there were significant decreases in RE at week 24, in REE and Ntotal (total number of enhancing voxels)*IRE (initial rate of enhancement) at weeks 12, 24 and 48, and in Ntotal*ME (maximal enhancement) at weeks 24 and 48. Mean BME decreased from baseline to week 48, and bone erosions did not progress. The patients’ clinical parameters significantly improved from baseline until week 48.ConclusionTCZ in combination with DMARDs improved wrist synovitis, BME and clinical parameters, without any progression in bone erosions. The RAMRIS for synovitis rapidly improved from as early as two weeks after the first TCZ infusion. (Funded by F. Hoffmann–La Roche; ACTRACE EudraCT No. 2009 012185-32).

Optimise: An Austrian Multicentre Study on the Effectiveness and Safety of Tocilizumab in Combination with Methotrexate versus Tocilizumab for Mild/Moderate Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Additional tocilizumab treatment led to improvement in patients with mild/moderate rheumatoid arthritis. The study results give no indication that the combination of Tocilizumab with Methotrexate induces a better outcome (preserving the level of disease activity achieved at week 12) in comparison with Tocilizumab monotherapy in patients corresponding to those included into the study.

A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

Patterns of Prednisone Use in Patients with Rheumatoid Arthritis Initiating Treatment with Tocilizumab in Routine US Clinical Practice.

IntroductionPrednisone is frequently administered in combination with other therapies for the treatment of rheumatoid arthritis (RA); however, its chronic use is associated with an increased risk of comorbidities and mortality. The objective of this analysis was to evaluate changes in prednisone use among patients with RA treated with tocilizumab (TCZ) in routine US clinical practice.MethodsTCZ-naïve patients in the Corrona RA registry who initiated TCZ were included. The primary outcome was the proportion of patients with changes in prednisone use over 12 months (primary analysis) and 6 months (secondary analysis). Changes in disease activity over 6 and 12 months (± 3 months) were assessed using the Clinical Disease Activity Index (CDAI). Outcomes were assessed in the overall population and separately for patients receiving TCZ monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs.ResultsOf patients receiving prednisone at baseline (mean [SD] dose: 7.7 [5.2] mg/day), 30.6% discontinued prednisone over 12 months; among patients receiving > 7.5 mg of prednisone at the time of TCZ initiation, 63.0% discontinued prednisone or decreased their dose by ≥ 5 mg over 12 months. In secondary analyses, 29.7% of patients receiving prednisone at baseline had discontinued prednisone over 6 months; among those receiving > 7.5 mg of prednisone at baseline, 51.3% discontinued or decreased their dose by ≥ 5 mg over 6 months. Changes in prednisone use and improvement from baseline in CDAI score over 6 and 12 months were comparable between patients who initiated TCZ monotherapy vs. TCZ combination therapy.ConclusionsIn this real-world analysis, many patients initiating TCZ monotherapy or combination therapy were able to discontinue or decrease their prednisone dose over 12 months. Similar changes in prednisone dose were observed over 6 months.Trial RegistrationClinicalTrials.gov identifier, NCT01402661.FundingCorrona, LLC and Genentech, Inc.Plain Language SummaryPlain language summary available for this article.

PMS12 TOCILIZUMAB IN MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS: SYSTEMATIC REVIEW OF EFFICACY AND SAFETY

The objective of this systematic review was to assess efficacy and safety of tocilizumab versus placebo in patients with moderate-to-severe active rheumatoid arthritis (RA) and with inadequate response to disease-modifying antirheumatic drugs (DMARDs). The subpopulation of special interest was patients with moderate RA. Medline, Embase and CENTRAL databases were searched through October 2018, following a review protocol prepared a priori. Search criteria covered keywords for rheumatoid arthritis and tocilizumab. Published (in English and Polish) and unpublished randomized controlled trials (RCTs) for tocilizumab versus placebo in RA were included. The risk of bias was assessed according to Cochrane Handbook. Seven included RCTs (Baek 2018, CHARISMA, LITHE, MEASURE, OPTION, ROSE and TOWARD study) assessed the efficacy and safety of tocilizumab+DMARDs versus placebo+DMARDs. Meta-analysis for the proportion of ACR20, ACR50 and ACR70 responders showed significantly higher rate in the tocilizumab group than in the placebo group at week 24 (OR (95%CI)= 3.75 (2.87, 4.89), 3.91 (2.57, 5.96) and 7.70 (5.35, 11.08) respectively). The mean DAS28 change was also significantly higher in the tocilizumab group. For the moderate RA subpopulation there was data on-file available from TOWARD study. Results prove, that in this group of patients tocilizumab is also more effective than placebo (statistically significant difference in ACR20, ACR50 and ACR70 rate at week 24, OR (95%CI)=4.86 (2.31, 10.22), 5.07 (1.95, 13.16) and 6.59 (1.45, 29.88) respectively). Safety profile of tocilizumab in moderate-to-severe RA patients is acceptable (no difference versus placebo in deaths, serious adverse events related to the drug or serious adverse events rate). In the moderate RA subgroup, safety profile is similar. Tocilizumab in combination with DMARDs reduced disease activity over 24 weeks more significantly and rapidly when compared to placebo+DMARDs. This high efficacy is proven both in moderate-to-severe RA and moderate RA subgroup.

Tocilizumab Patterns of Use, Effectiveness, and Safety in Patients with Rheumatoid Arthritis: Final Results from a Set of Multi-National Non-Interventional Studies.

IntroductionThe objective of this study was to observe the patterns of usage, efficacy, and safety of tocilizumab (TCZ) in clinical practice in patients with rheumatoid arthritis.MethodsData on the real-world usage, efficacy, and safety of TCZ were collected from patients during routine follow-up visits conducted over a 6-month period. Patients were grouped by previous exposure to biologic therapies (biologic exposed vs. biologic naive).ResultsOf 1912 patients enrolled from 16 countries, 639 (33.4%) received TCZ monotherapy and 1273 (66.6%) received TCZ combination therapy. At baseline, 1073 patients (56.1%) were biologic naive and 839 (43.9%) were biologic exposed. At 6 months, 1504 patients (78.7%) continued to receive TCZ treatment, with no descriptive differences in retention rates between biologic-exposed and biologic-naive patients and between patients receiving TCZ monotherapy or combination therapy. Dose and use of methotrexate and prednisone were reduced at 6 months. Efficacy at 6 months, including patient-reported outcomes, was demonstrated in both biologic-naive and biologic-exposed groups. Adverse events (AEs) occurred in 817 patients [42.7%; incidence rate: 179 events per 100 patient-years (PY)], and serious AEs (SAEs) occurred in 118 patients (6.2%; 17 events per 100 PY), with comparable rates of AEs and SAEs between subgroups.ConclusionIn routine clinical practice, TCZ discontinuation rates were low and unaffected by prior use of biologics. Effectiveness was similar between groups, and no new safety signals were identified.FundingF. Hoffmann-La Roche.Electronic supplementary materialThe online version of this article (10.1007/s40744-019-0150-x) contains supplementary material, which is available to authorized users.

PSY44 - TOCILIZUMAB IN COMBINATION WITH CORTICOSTEROIDS FOR THE TREATMENT OF GIANT CELL ARTERITIS: A BUDGET IMPACT ANALYSIS IN ITALY

To estimate the economic impact of tocilizumab (TCZ) administered weekly in combination with a 26-week prednisone taper regimen, for the treatment of giant cell arteritis (GCA), in the Italian market. A deterministic semi-Markov model was developed to simulate the evolution of GCA patients in Italy for 3 years. Baseline characteristics, transition probabilities and event rates were modelled according to the results of the phase III trial GiACTA. A comprehensive third-party payer perspective encompassing only direct health costs (drugs, resources consumption, and adverse events management) was adopted to evaluate the switch of all patients, currently treated with prednisone alone, to the new combination regimen of TCZ + prednisone. Target patients were estimated for 2019-2021 starting from Italian population (>50 years) applying national epidemiologic data and considering only patients eligible to receive TCZ. In the next three years 1,314 patients are expected to be treated: 161 in the first, 492 in the second and 661 in the third year of analysis. The switch to TCZ combination therapy results in an increase in the total cost of less than 15 million Euro for 3 years corresponding to 11,250 Euro/patient yearly. If the therapy adherence is included, the economic impact reduces to less than 12 million Euro for 3 years, corresponding to 8,775 Euro/patient yearly. Treatment cost of GCA depends almost completely on pharmacological therapy. Changes in the current prescription scenario, with the adoption of TCZ, have a sustainable economic impact; in particular, considering a realistic adherence.

The Use of Tocilizumab in Combination with Methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

Background Aim of this research is to assess the efficacy and safety of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response to non-biologic DMARDs.Methods This was a interventional, prospective, single arm, multicenter, study in  Indonesian male or female patients aged ≥ 18 years old, with a diagnosis of RA for &gt; 6 months based on ACR 1987 revised criteria with moderate to severe disease activity (DAS28 score &gt; 3.2) after ≥ 12 weeks of non-biologic DMARDs treatment. The treatment consisted of tocilizumab, 8 mg/kg, intravenous (IV), every 4 weeks for a total of 6 infusion in combination with oral MTX (10−25 mg) every week. Efficacy was assessed based on the percentage of patients achieving low disease activity state (DAS28 &lt; 3.2), percentage of patients achieving reduction &gt; 1.2 point of DAS28, percentage of patients achieving remission (DAS28 &lt; 2.6), and percentage of patients with ACR20, ACR50, and ACR70 responses. Descriptive statistics will be used for presentation of results.Results 100% patients reached low disease activity (DAS28 ≤ 3.2) at last study visit (week 24) and clinically significant improvement (reduction at least 1.2 units) at every visit in DAS28, both for ITT or PP patients. Remission (DAS28 &lt; 2.6) was observed in 82.1% (ITT patients) and 93.1 % (PP patients) on last study visit. ACR20, ACR50, and ACR70 were achieved in 20%, 34%, and 34% (ITT patients), and 7%, 24%, and 62% (PP patients) on week 24. There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis. Most common adverse events were hepatic dysfunction (30.7%), hypercholesterolemia (23.1%), followed by arthralgia (20.5%) Twelve percent of patients needed dose modification due to elevated liver enzyme (elevated ALT/SGPT level).Conclusion Tocilizumab seems to be efficacious and likely to have good safety profile in non- biologic DMARD nonresponsive RA patients of PICTURE INA study.   Keywords: Rheumatoid Arthritis, Tocilizumab, DMARD, DAS28

The Use of Tocilizumab in Combination with Methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

Background Aim of this research is to assess the efficacy and safety of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response to non-biologic DMARDs.Methods This was a interventional, prospective, single arm, multicenter, study in Indonesian male or female patients aged ≥ 18 years old, with a diagnosis of RA for &gt; 6 months based on ACR 1987 revised criteria with moderate to severe disease activity (DAS28 score &gt; 3.2) after ≥ 12 weeks of non-biologic DMARDs treatment. The treatment consisted of tocilizumab, 8 mg/kg, intravenous (IV), every 4 weeks for a total of 6 infusion in combination with oral MTX (10−25 mg) every week. Efficacy was assessed based on the percentage of patients achieving low disease activity state (DAS28 &lt; 3.2), percentage of patients achieving reduction &gt; 1.2 point of DAS28, percentage of patients achieving remission (DAS28 &lt; 2.6), and percentage of patients with ACR20, ACR50, and ACR70 responses. Descriptive statistics will be used for presentation of results.Results 100% patients reached low disease activity (DAS28 ≤ 3.2) at last study visit (week 24) and clinically significant improvement (reduction at least 1.2 units) at every visit in DAS28, both for ITT or PP patients. Remission (DAS28 &lt; 2.6) was observed in 82.1% (ITT patients) and 93.1 % (PP patients) on last study visit. ACR20, ACR50, and ACR70 were achieved in 20%, 34%, and 34% (ITT patients), and 7%, 24%, and 62% (PP patients) on week 24. There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis. Most common adverse events were hepatic dysfunction (30.7%), hypercholesterolemia (23.1%), followed by arthralgia (20.5%) Twelve percent of patients needed dose modification due to elevated liver enzyme (elevated ALT/SGPT level).Conclusion Tocilizumab seems to be efficacious and likely to have good safety profile in non- biologic DMARD nonresponsive RA patients of PICTURE INA study. Keywords: Rheumatoid Arthritis, Tocilizumab, DMARD, DAS28

IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment. This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells. In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-κB pathway. Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.

TAFRO syndrome with refractory thrombocytopenia responding to tocilizumab and romiplostim: a case report.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome is a unique clinicopathologic subtype of multicentric Castleman's disease that has recently been identified in Japan. However, little is known about its renal histological changes and the optimal treatment for TAFRO syndrome. An 80-year-old Japanese woman was admitted to our hospital for evaluation of severe anasarca and weight gain (10kg in a month). She had polyneuropathy, monoclonal plasma cell proliferative disorder with positive kappa M-protein, a sclerotic bone lesion, elevation of vascular endothelial growth factor (VEGF), skin changes, and extravascular volume overload, which fulfilled the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, and monoclonal protein, skin changes) syndrome. However, kappa-type M-protein and thrombocytopenia with positivity of platelet-associated immunoglobulin G antibody were unusual, and fitted the diagnostic criteria for TAFRO syndrome. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis with endothelial swelling and the infiltration of monocytes and neutrophils without specific immunoglobulin deposits. Her systemic symptoms were refractory to initial treatment with high-dose melphalan and glucocorticoids. Alternative therapy with an anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) effectively controlled the symptoms, while a thrombopoietin receptor agonist (romiplostim) was effective for her thrombocytopenia. Results suggest that IL-6-VEGF axis and an autoimmune mechanism may be responsible for TAFRO syndrome with clinical features of POEMS and refractory thrombocytopenia, which can be successfully treated with combination of tocilizumab and romiplostim.

Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial

ObjectiveInvestigate whether the efficacy and safety of intravenous tocilizumab (TCZ) demonstrated at week 52 in patients with early rheumatoid arthritis (RA) are maintained to week 104.MethodsMethotrexate (MTX)-naive patients with early...

Is Methotrexate (MTX) Necessary in Combination Therapy with Tocilizumab and MTX for Rheumatoid Arthritis in Remission? Cohort Study Carried by the Michinoku Tocilizumab Study Group

Objectives: To determine the necessity of methotrexate (MTX) in patients with rheumatoid arthritis (RA) achieving clinical remission treated by tocilizumab (TCZ) and MTX (TCZ+MTX). Methods: A 3 year, multicenter, observational cohort study was performed. RA patients were treated by TCZ with or without MTX depending on the attending doctor’s decision. Of the patients treated with TCZ+MTX, the patients who discontinued MTX after achieving clinical remission (discontinued group: DISC) were compared with those who maintained the same dose of MTX after achieving clinical remission (maintained group: MAIN). Results: The DISC and MAIN consisted of 33 patients and 37 patients, respectively. The mean DAS28-ESR was significantly lower in the DISC than in the MAIN at 3 months, 6 months and 9 months (3 months: 1.8 ± 0.8 and 2.4 ± 1.0, p=0.018, 6 months: 1.5 ± 0.7 and 2.2 ± 1.0, p=0.009 and 9 months: 1.4 ± 0.6 and 2.0 ± 1.0, p=0.008, respectively). The DAS28-ESR remission rate and Boolean remission rate were significantly higher in the DISC than in the MAIN (93.8% and 64.5%, respectively in the DAS28-RSR, p=0.04; 51.6% and 17.2%, respectively in the Boolean, p=0.005) at 6 months. Conclusions: RA patients treated by the combination of TCZ and MTX who achieved deep remission (DAS28- ESR ≤ 1.98) at as early as 3 months could discontinue taking MTX.

Comparative effectiveness of biologics for the management of rheumatoid arthritis: systematic review and network meta-analysis.

Our aim was to establish the comparative effectiveness of rheumatoid arthritis (RA) biologics, using a systematic review and network meta-analysis. The systematic review used randomized controlled trials (RCTs) in adults with RA who failed treatment with conventional disease-modifying agents for rheumatoid disease (cDMARDs). We compared the effectiveness of abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and rituximab to tocilizumab, a recent biologic with a different mechanism of action (anti-IL-6 receptor). A network meta-analysis (NMA) included the indirect and direct evidence previously selected. In total, 207 articles were included describing 68 RCTs. The NMA showed that tocilizumab monotherapy was superior to standard care (ACR20, OR 13.27, 95% CrI [3.958, 43.98]; ACR50, 17.45 [10.18, 31.24]; ACR70, 37.77 [7.226, 216.3]; EULAR, 10.42 [1.963, 54.8]); and methotrexate (MTX; ACR50, OR 5.44 [4.142, 7.238]; ACR70, 7.364 [1.4, 30.83]; EULAR, 4.226 [1.184, 15.58]) at 26weeks. Similarly, the combination of tocilizumab + MTX was significantly better than standard care/placebo and MTX alone for ACR20, ACR50, ACR70, and EULAR at 26weeks (OR 18.63 [5.32, 66.81]; 24.27 [14.5, 41.91]; 46.13 [10.08, 277]; 14.23 [2.493, 84.02]; 4.169 [2.267, 7.871]; 5.44 [4.142, 7.238]; 8.731 [4.203, 19.29]; 7.306 [4.393, 13.04], respectively). At 52weeks, compared to MTX alone, tocilizumab + MTX was significantly better for ACR20 and ACR50 response. Few significant differences were found between tocilizumab (alone or in combination) and any other biologics. Results must be considered in context with the limitations of the available evidence. This NMA suggests that tocilizumab was superior to cDMARDs and as effective as other biologics for RA.