Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Low immunogenicity of tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK). RESULTS: The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy. CONCLUSIONS: The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

Patterns of tocilizumab use, effectiveness and safety in patients with rheumatoid arthritis: core data results from a set of multinational observational studies.

OBJECTIVES: To observe patients with rheumatoid arthritis (RA) treated with the interleukin-6 receptor-alpha inhibitor tocilizumab (TCZ) in routine clinical practice. METHODS: Data on concomitant medications, effectiveness and safety were pooled from independent, multinational studies in patients with RA initiating intravenous TCZ according to local label recommendations observed in routine practice for 6 months. Patients were grouped by TCZ monotherapy or combination therapy with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). The primary endpoint was the proportion of patients receiving TCZ after 6 months. RESULTS: Of 1336 patients enrolled, 506 (37.9%) received TCZ monotherapy and 830 (62.1%) received combination therapy. Kaplan-Meier analysis estimated that 80% (95% CI, 76%-83%) of monotherapy and 87% (95% CI, 84%-89%) of combination therapy patients continued to receive TCZ at 6 months (log-rank p<0.001). During the observation period, TCZ was discontinued by 113 (22.3%) monotherapy patients and 116 (14.0%) patients on combination therapy. The mean prednisone-equivalent oral corticosteroid dose was 8.4 mg/day for monotherapy and combination therapy patients at baseline and 7.7 and 7.6 mg/day, respectively, at month 6. Adverse events or laboratory abnormalities requiring TCZ dose modification were reported for 66 (13.0%) monotherapy and 130 (15.7%) combination therapy patients. Effectiveness at 6 months was similar between groups; mean (SD) change from baseline in Clinical Disease Activity Index (CDAI) was -20.3 (14.18) for monotherapy and -22.3 (16.09) for combination therapy (p=0.7347). CONCLUSIONS: In routine clinical practice, 38% of patients received TCZ as monotherapy. Persistence on monotherapy or in combination therapy with csDMARDs was high, with a slight trend towards a higher rate with combination therapy, and effectiveness was similar between groups.

Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis.

The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at ≥1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were ρ = 0.50 at baseline and ρ = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information.

Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study.

BACKGROUND: As recommended in the current prescribing information, rituximab infusions in patients with rheumatoid arthritis (RA) take 4.25 hours for the first infusion and 3.25 hours for subsequent infusions, which is a burden on patients and the health care system. We therefore evaluated the safety of infusing rituximab at a faster rate for an infusion period of 2 hours in patients with RA. METHODS: Patients with an inadequate response to anti-TNF who were rituximab-naive or -experienced received 2 courses of rituximab: Infusion 1 (Day 1) was administered over the standard 4.25 hours, and Infusions 2 (Day 15), 3 (Day 168) and 4 (Day 182) were administered over a faster 2-hour period. The primary endpoint was incidence of infusion-related reactions (IRRs) associated with Infusion 2. RESULTS: Of the 351 patients enrolled, 87% and 13% were rituximab-naive and -experienced, respectively. The incidence (95% CI) of IRRs associated with Infusion 1 was 16.2% (12.5%, 20.5%) and consistent with weighted historical incidence of 20.7% (19.4%, 22.1%). The incidence (95% CI) of IRRs associated with Infusions 2, 3, and 4 compared with respective weighted historical incidences at the standard infusion rate was 6.5% (4.1%, 9.7%) vs 8.1% (7.2%, 9.1%); 5.9% (3.5%, 9.3%) vs 11.5% (10.3%, 12.8%); and 0.7 (0.1%, 2.6%) vs 5.0% (4.2%, 6.0%), respectively. All IRRs were grade 1 or 2, except for 3 grade 3 IRRs associated with Infusion 1 and 2 grade 3 IRRs associated with Infusion 2. Four patients experienced a total of 5 grade 3 IRRs; 3 of these patients continued on to received subsequent infusions at the faster rate. There were no serious IRRs. CONCLUSION: This study demonstrated that rituximab can be administered at the faster infusion rate at the second and subsequent infusions without increasing the rate or severity of IRRs.

Comparative Efficacy (DAS28 Remission) of Targeted Immune Modulators for Rheumatoid Arthritis: A Network Meta-Analysis.

INTRODUCTION: The objective of this study was to evaluate the relative efficacy of targeted immune modulators (TIMs) in TIM-naïve/mixed populations (≤ 20% TIM-experienced) and TIM-experienced (> 20% TIM-experienced) adults with moderate-to-severe rheumatoid arthritis with an inadequate response to or intolerance of conventional disease-modifying antirheumatic drugs (cDMARDs). METHODS: A fixed-effects Bayesian network meta-analysis (NMA) was performed using published study-level data from 41 randomized controlled trials (RCTs) identified from two recent systematic literature reviews conducted by the Institute for Clinical and Economic Review, and two additional phase III trials for filgotinib (FINCH-1, FINCH-2). RCTs that compared TIMs with each other, cDMARD therapy, or placebo were included. Treatments included Janus kinase (JAK) inhibitors, tumor necrosis factor α inhibitors (TNFi), and other non-TNFi therapies. Efficacy was defined as achieving remission with a DAS28 score < 2.6 at 12 and 24 weeks. RESULTS: In the 12-week analysis for the TIM-naïve/mixed population, all TIMs combined with cDMARD therapy were significantly more likely to achieve remission compared with a cDMARD alone, with intravenous tocilizumab showing a substantially greater magnitude of effect (odds ratio 19.36; 95% credible interval 11.01-38.16). Similarly, in the 24-week analysis, intravenous and subcutaneous tocilizumab showed the highest odds ratio of achieving DAS28 remission compared with cDMARD therapy. Similar trends were observed for the analyses on monotherapy or TIM-experienced population. CONCLUSIONS: This NMA demonstrated that tocilizumab is associated with a greater likelihood of remission (DAS28 < 2.6) at 12 and 24 weeks compared with most other TIMs, including new JAK inhibitors, when used in combination with a cDMARD or as monotherapy among TIM-naïve/mixed or TIM-experienced populations.

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

INTRODUCTION: Understanding 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. METHODS: TCZ 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. RESULTS: Among 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. CONCLUSIONS: Median 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 REGISTRATION: ClinicalTrials.gov identifier, NCT01402661.

Magnetic Resonance Imaging (MRI) Results Following Discontinuation of Methotrexate in Rheumatoid Arthritis Treated with Subcutaneous Tocilizumab: The COMP-ACT MRI Substudy.

OBJECTIVE: To assess differences in joint damage and inflammation using magnetic resonance imaging (MRI) between patients with rheumatoid arthritis (RA) who achieved low disease activity with tocilizumab (TCZ) + methotrexate (MTX) and subsequently continued or discontinued MTX. METHODS: In the COMP-ACT trial, US patients with RA received subcutaneous TCZ 162 mg + MTX. Those who achieved 28-joint count Disease Activity Score calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to discontinue MTX (TCZ monotherapy; mono) or continue TCZ + MTX until Week 52. In a subset of patients, 1.5-Tesla MRI was used to obtain images of bilateral hands and wrists at weeks 24 and 40. Outcomes included changes in MRI-assessed synovitis, osteitis, erosion, and cartilage loss from Week 24 to Week 40, and in the proportion of patients with progression of each score. RESULTS: Of 296 patients who achieved DAS28-ESR ≤ 3.2 at Week 24, 79 were enrolled in the pilot MRI substudy and randomized to TCZ mono (n = 38) or TCZ + MTX (n = 41). Treatment with either TCZ mono or TCZ + MTX suppressed erosion progression, synovitis, osteitis, and cartilage loss. The proportion of patients with no progression in each outcome measure was similar between groups (range, TCZ mono: 84.8-97.0%; TCZ + MTX: 92.3-100%). CONCLUSION: In a subset of patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal in intraarticular inflammation and damage measures in patients who discontinued MTX versus those who continued TCZ + MTX.

Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial.

OBJECTIVE: To evaluate whether tocilizumab (TCZ) monotherapy is noninferior to treatment with TCZ plus methotrexate (MTX) for maintaining clinical responses in patients with rheumatoid arthritis (RA) in whom low disease activity is achieved with TCZ plus MTX. METHODS: Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneously. At 24 weeks, patients who achieved a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of ≤3.2 were randomized to receive TCZ monotherapy or to continue treatment with TCZ plus MTX until week 52. The primary outcome measure was the comparison of the mean change in the DAS28-ESR from week 24 to week 40 between the TCZ monotherapy and TCZ plus MTX arms (noninferiority margin of 0.6). Secondary outcome measures included worsening of the DAS28-ESR by ≥1.2, achievement of a DAS28-ESR of <2.6 and ≤3.2, and safety and immunogenicity. RESULTS: Among the 718 patients enrolled, 296 were randomized at week 24 to receive TCZ monotherapy (n = 147) or TCZ plus MTX (n = 147). The mean changes in the DAS28-ESR from week 24 to week 40 were 0.46 and 0.14 in the TCZ monotherapy arm and the TCZ plus MTX arm, respectively (weighted difference between the groups, 0.318 [95% confidence interval 0.045, 0.592]); discontinuing MTX in TCZ responders was noninferior to continuing MTX. Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, which occurred in 2.1% of patients in the TCZ monotherapy group and 2.2% of patients receiving TCZ plus MTX. CONCLUSION: Patients with RA receiving TCZ plus MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity during the 16 weeks following MTX discontinuation.

Routine Assessment of Patient Index Data 3 and the American College of Rheumatology/European League Against Rheumatism Provisional Remission Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial With Tocilizumab.

OBJECTIVE: The American College of Rheumatology/European League Against Rheumatism established definitions of remission for rheumatoid arthritis (RA) based on composite scores, including tender (TJC) and swollen joint counts (SJC), patient global visual analog scale (VAS) score, laboratory tests, and, in the Simplified Disease Activity Index (SDAI), the physician global score. Time constraints on a physician's schedule demand an easy yet accurate tool to measure disease activity. We assessed the predictive ability of the Routine Assessment of Patient Index Data 3 (RAPID3) with and without a single swollen joint versus the SDAI and/or Boolean remission criteria for functional and radiographic outcomes. METHODS: Data were from the Tocilizumab Safety and the Prevention of Structural Joint Damage phase III trial in RA patients. We assessed the ability at year 1 of a RAPID3 score of ≤3 + 1 SJC, RAPID3 score of ≤3 (remission) without SJC, SDAI score of ≤3.3 (remission), and/or Boolean remission (SJC, TJC, patient global VAS, and C-reactive protein level [mg/dl] all ≤1) to predict year 2 Health Assessment Questionnaire (HAQ) disability index (DI) score of ≤0.5 (normal), no worsening of HAQ DI score from year 1, and no worsening of Genant-modified Total Sharp Score from year 1. RESULTS: Among 690 patients, the mean ± SD baseline Disease Activity Score in 28 joints was 6.5 ± 0.96, RAPID3 score was 14.2 ± 5.51, and the SDAI score was 41.7 ± 13.01. Achieving year 1 measures was associated with good functional and radiographic outcomes at year 2. Sensitivity, specificity, positive predictive values, and negative predictive values were 49.1%, 83.2%, 37.4%, and 88.9% (RAPID3 remission); 26.4%, 91.7%, 36.8%, and 87.1% (RAPID3 + 1 SJC); 26.7%, 90.9%, 37.3%, and 85.9% (SDAI remission); and 17.0%, 96.6%, 47.4%, and 86.4% (Boolean remission), respectively. CONCLUSION: The predictive ability of RAPID3 (with or without joint count) was similar to that of SDAI and Boolean criteria.

Composite Indices Using 3 or 4 Components of the Core Data Set Have Similar Predictive Ability to Measure Disease Activity in RA: Evidence from the DANCER and REFLEX Studies.

Background. Understanding how disease-assessment indices perform in rheumatoid arthritis (RA) clinical trials can inform their use in routine practice. The study objective was to assess the capacity of combinations of RA Core Data Set measures to distinguish rituximab from control treatment. Methods. Post hoc analysis of two randomised clinical trials was used. Composite Efficacy Indices were derived by combining three or four RA Core Data Set measures from three possible sources: physician, patient, and laboratory. Results. All 105 Composite Efficacy Indices evaluated significantly distinguished rituximab from control treatment (P < 10(-7)). Generally, indices containing measures from three different sources had a greater capacity to distinguish rituximab from control treatment than indices containing three measures from one source. Composite Efficacy Indices performed as well as validated indices such as DAS28, RAPID3, and CDAI. Conclusions. All indices composed of three or four RA Core Data Set measures have a similar capacity to detect treatment differences. These results suggest that the precise measurement used is less important than whether any measurement is performed, although selection should be consistent for each patient. Therefore, the choice of assessment tool should not be limited to a prescribed list and should instead be left to the clinician's discretion.

Cytochrome P450 3A4 activity after surgical stress.

OBJECTIVE: To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. DESIGN: Prospective, open-label study with each patient serving as his or her own control. SETTING: University-affiliated, acute care, general hospital. PATIENTS: A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). INTERVENTIONS: Cytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. MEASUREMENTS AND MAIN RESULTS: ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p =.06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r(s) = -.541, p =.03) and log interleukin-6 area under the curve from 0 to 72 hrs (r(s) = -.597, p =.014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% +/- 5.2% vs. 74.7% +/- 5.1%, p <.001). CONCLUSIONS: Acute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.