Real-world Effectiveness of Sarilumab in RA: Results from the Open-label, Prospective, Single-arm Observational PROFILE Study.

INTRODUCTION: The 1-year PROspective sarilumab (preFILled syringe/pen) multinational, obsErvational (PROFILE) study evaluated the real-world effectiveness and safety of sarilumab in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: Safety endpoints included adverse events (AEs) and lab abnormalities. Effectiveness endpoints included the ACR core set. The primary endpoint was the change from baseline in Clinical Disease Activity Index (CDAI). All statistics are descriptive and p values were nominal. RESULTS: In total, 595 patients were treated, of whom 223 (37.5%) received sarilumab monotherapy and 372 (62.5%) received combination therapy. Upon initiation of sarilumab, an improvement in the mean (SD) CDAI score was observed at week 24 [11.4 (10.3)] and was maintained through week 52 [10.0 (10.5)], resulting in a mean [SD] reduction of -14.9 (12.7) and -14.4 (12.9), respectively. There were consistent improvements in disease activity that were similar for patients on monotherapy vs. combination therapy. An increase in the proportion of patients achieving remission and low disease activity was reported. By week 52, both groups had improved physical function and quality of life. There were no new safety signals. The proportions of any patients reporting a treatment-emergent adverse event (TEAE) or serious treatment-emergent AE (SAE) was 66.2% and 5.9%, respectively, and were similar between both treatment groups. Overall, 15.6% of patients discontinued sarilumab treatment due to TEAEs. The most commonly reported TEAE of interest was neutropenia (14.1%). CONCLUSIONS: In this 1-year, observational real-world study, sarilumab therapy resulted in improved clinical outcomes. The safety profile was consistent with that observed in sarilumab randomized clinical trials. This study was entered on the German website (Paul Ehrlich Institute) on January 11, 2018, with NIS No.: 423.

Investigating the impact of Tocilizumab, Sarilumab, and Anakinra on clinical outcomes in COVID-19: A systematic review and meta-analysis.

Background: Monoclonal antibodies (mAbs) are currently under investigation as a potential therapeutic option for COVID-19. Clinical trials are examining their efficacy in lowering mortality rates and the requirement for mechanical ventilation (MV). It is necessary to conduct a thorough examination of current randomized controlled trials (RCTs) in order to provide more definitive evidence on their effectiveness for COVID-19 patients. This meta-analysis aims to analyze RCT results on the impact of three mAbs (Anakinra, Sarilumab, Tocilizumab) on COVID-19 patient outcomes. Method: The meta-analysis was conducted in accordance with the PRISMA guidelines. Eligible RCTs were conducted to evaluate the effectiveness of three mAbs in treating patients with COVID-19. These trials were identified by searching various databases up to April 1, 2024. In total, this meta-analysis incorporated 19 trials with a total of 8097 patients. Pooled relative risk and studies' heterogeneity were assessed by statistical analysis, which involved the use of fixed effects models and subgroup analysis. Result: The administration of mAbs (Tocilizumab, Sarilumab, and Anakinra) showed various results in the management of COVID-19 patients. While the overall pooled data did not reveal a significant reduction in the need for MV, the study found that the use of mAbs was associated with a decreased risk of clinical worsening (pooled relative risk: 0.75, 95 % CI [0.59, 0.94], p = 0.01) and an increased probability of discharging COVID-19 patients by day 28 or 29 (pooled relative risk: 1.17, 95 % CI [1.10, 1.26]). Notably, the subgroup analysis revealed that Tocilizumab had a significant effect in reducing the risk of clinical worsening compared to Sarilumab. Additionally, the analysis of mortality outcomes indicated that the administration of mAbs had the potential to decrease the overall risk of mortality over time (pooled RR: 0.90, 95 % CI [0.83, 0.97], p = 0.01). Conclusion: In summary, our meta-analysis suggests that mAbs, particularly Tocilizumab, may play a valuable role in managing COVID-19 by reducing the risk of clinical worsening, improving hospital discharge rates, and decreasing mortality.

Assessment of adverse events related to anti-interleukin-6 receptor monoclonal antibodies using the FDA adverse event reporting system: a real-world pharmacovigilance study.

BACKGROUND: Interleukin-6 (IL-6) monoclonal antibodies are commonly acknowledged for their efficacy in managing coronavirus disease 2019 (COVID-19); however, there remains a paucity of comprehensive studies on their potential adverse effects. RESEARCH DESIGN AND METHODS: This is a retrospective pharmacovigilance investigation. We employed FAERS using OpenVigil FDA to detect adverse reactions linked to the interleukin-6 antagonist tocilizumab and sarilumab. RESULTS: Completely 67,976 reports were identified as 'primary suspected (PS)' adverse events (AEs) for tocilizumab, and 12,560 reports for sarilumab. 109 significant disproportionality preferred terms (PTs) of tocilizumab and 158 PTs of sarilumab were retained. A higher incidence of adverse reactions occurred in females aged 45-64 years, with a higher rate of subsequent hospitalization. Both drugs exhibited adverse reactions consistent with previously reported side effects, such as leukopenia, elevated liver enzymes, and hypercholesterolemia. Additionally, there was a strong correlation with gastrointestinal issues. Unexpected significant adverse events, including diabetes, fluctuations in blood pressure, drug ineffectiveness, malignancies, and disorders of the nervous system, were also observed. Gender and age differences existed in AEs signals related to IL-6RAs. CONCLUSION: Our study identified significant new AE signals for interleukin-6 receptor antagonists, potentially supporting clinical monitoring and risk identification for this class of drugs.

Efficacy of sarilumab and dexamethasone co-administration for lowering multiple blood biomarkers in the treatment of cytokine release syndrome in hospitalized COVID-19 patients.

The current study was planned to explore the potential synergistic role of the co-administration of sarilumab and dexamethasone in reducing blood biomarkers associated with cytokine release syndrome in hospitalised patients of coronavirus disease-2019. The sample comprised 22 patients hospitalised with severe and critical severity levels and who were treated with sarilumab and dexamethasone. Positive responses were seen in blood biomarkers, including decreased interleukin-6 alpha levels and improved oxygen saturation. Tumour necrosis factor, Ddimer, C-reactive protein, ferritin and lymphocyte count also showed positive responses in patients who survived than those who died. Lactate dehydrogenase levels fluctuated with improvement among the survivors, but had limited effectiveness in those who died. The findings suggested promising avenues for future treatment strategies in patients with severe coronavirus disease-2019 and cytokine release syndrome.

The effects of sarilumab as monotherapy and in combination with non-methotrexate disease-modifying anti-rheumatic drugs on unacceptable pain in patients with rheumatoid arthritis: a post-hoc analysis of the HARUKA phase 3 study.

OBJECTIVES: To investigate unacceptable pain (UP; visual analogue scale [VAS] >40 mm) and uncontrolled inflammation (C-reactive protein [CRP] ≥1.0 mg/dL) in patients with active rheumatoid arthritis (RA) receiving sarilumab (SAR) as monotherapy or in combination with non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (SAR+csDMARDs). METHODS: In the HARUKA phase 3 study (NCT02373202), Japanese patients received either SAR monotherapy (n=61) or SAR+csDMARDs (n=30). In this post-hoc analysis, changes in the proportions of patients with/without UP and controlled/uncontrolled inflammation were assessed over 52 weeks. RESULTS: At baseline, 80.3% (49/61) of patients receiving SAR monotherapy had UP and this proportion decreased with treatment to 55.9% (33/59) at Week 4 and 15.5% (9/58) at Week 52. The SAR+csDMARDs group achieved a reduction in UP from 73.3% (22/30) at baseline to 34.5% (10/29) at Week 4 and 0% (0/24) by Week 52. At baseline, 34.4% (21/61) and 50% (15/30) of patients had both UP and uncontrolled inflammation in the SAR monotherapy and SAR+csDMARDs groups; by Week 2, the proportions decreased to 6.6% (4/61) and 3.3% (1/30), respectively; and 0% in both groups by Week 52. CONCLUSION: UP and inflammation were reduced in patients with active RA in Japan in both SAR monotherapy and SAR+csDMARDs treatment groups.

Efficacy and safety of sarilumab in patients with rheumatoid arthritis stratified by age (<65 and ≥65 years): A post-hoc analysis of Japanese phase 3 clinical trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of sarilumab in older patients with active rheumatoid arthritis (RA). METHODS: This is a post-hoc analysis of KAKEHASI (NCT02293902) and HARUKA (NCT02373202) trials with stratification by age (<65 and ≥65 years). Patients with moderately-to-severely active RA were treated with sarilumab in combination with methotrexate (MTX) or with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy. The primary endpoints in KAKEHASI and HARUKA trials were the American College of Rheumatology 20% improvement criteria (ACR20) responses at Week 24 and safety, respectively. Secondary endpoints were other RA disease activity measures, including Clinical Disease Activity Index (CDAI). RESULTS: Approximately 20% of patients were aged ≥65 years in treatment arms across both trials, except the sarilumab+csDMARDs arm (40%, 12/30). ACR20 response rates were similar between age groups across sarilumab treatment arms and similar results were obtained for CDAI scores. Safety profiles were similar between age groups except for a higher incidence of serious adverse events in patients aged ≥65 years in the sarilumab+MTX arm. CONCLUSIONS: In Japanese patients with RA enrolled in phase 3 studies for sarilumab, no clear difference in efficacy or safety was observed between patients aged <65 and ≥65 years.

Investigational agents for polymyalgia rheumatica treatment: assessing the critical needs for future development.

INTRODUCTION: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder characterized by pain and stiffness in the shoulder and pelvic girdles, constitutional symptoms, and elevated acute-phase reactants. Glucocorticoids (GCs) remain the first-choice treatment for PMR, but relapses are common. Identification of steroid-sparing agents is therefore of utmost importance. AREAS COVERED: The efficacy of conventional immunosuppressive drugs is controversial. The use of interleukin (IL)-6 receptor inhibitors proved to be effective and safe in treating PMR patients. Currently, there are 12 ongoing clinical trials exploring potential treatments such as leflunomide, low-dose IL-2, rituximab, abatacept, secukinumab, Janus kinase inhibitors, and selective inhibitors like SPI-62 and ABBV 154. EXPERT OPINION: The high efficacy of IL-6 R receptor inhibitors as well as the numerous drug trials currently recruiting suggest that several therapeutic options will be available in the near future. Accurate diagnosis and early stratification of PMR patients according to the giant cell arteritis-PMR Spectrum Disease 'GPSD' and potential risk factors for relapsing disease or GC-related adverse events are crucial to identify patients who would benefit most from GC-sparing agents. The development of internationally accepted definitions for remission and relapse is urgently needed. Early referral strategies to specialist settings would improve disease stratification and personalized treatment.

Safety of sarilumab in a Japanese population with rheumatoid arthritis by age group: Data from an interim analysis of a post-marketing surveillance study.

OBJECTIVES: Using data from a post-marketing surveillance, this interim subgroup analysis investigated the safety of sarilumab in younger (<65 years) and older patients (≥65 and ≥75 years) with rheumatoid arthritis. METHODS: During this interim analysis, patients who were treated with sarilumab in Japan were enrolled between June 2018-2021. Data collected by 12 January 2022 were analysed, with adverse drug events monitored over 52 weeks. RESULTS: Of 972 patients with available data, proportion of patients aged <65 years, ≥65 years and ≥75 years were 40.8%, 59.2% and 27.8%, respectively. Most patients (95.5%) received the standard 200 mg dose of sarilumab as the initial dose. Adverse drug reactions were reported in 24.6% of patients, with serious events accounting for 6.4% of cases. No malignancy and low incidences of adverse drug reactions of special interest were reported across all age groups (<65 years, 7.8%; ≥65 years, 8.2%; ≥75 years, 8.5%). When stratified by absolute neutrophil count above and below the lower limit of normal, there were no numerical differences in incidences of serious and non-serious infections between age groups. CONCLUSIONS: Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.

Cancer risk with tocilizumab/sarilumab, abatacept, and rituximab treatment in patients with rheumatoid arthritis: a Danish cohort study.

OBJECTIVES: To investigate cancer risk in rheumatoid arthritis (RA) patients treated with tocilizumab/sarilumab, abatacept, or rituximab compared with those who received tumour necrosis factor inhibitors (TNFi) and compared with biological disease-modifying anti-rheumatic drugs (bDMARD) naïve RA patients. METHODS: Nationwide registry-based cohort study of RA patients initiating treatment with tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive patients their second type of conventional synthetic DMARD (csDMARD). Patients were identified in DANBIO and followed for cancer from 2006-2020. Patients could contribute multiple treatments, with person years (PYRS), deaths, and cancers allocated to each treatment group in a 'latest type of treatment' manner. Inverse probability of treatment weighting and weighted cause-specific Cox models were used to calculate hazard ratios (HRs) for cancer in each tocilizumab/sarilumab, abatacept, and rituximab group compared with TNFI and bDMARD naïve groups, respectively. RESULTS: In total, 21 982 treatment initiations, 96 475 PYRS, and 1423 cancers were identified. There were no statistically significant increased HRs for overall cancer in tocilizumab/sarilumab, abatacept, or rituximab treatment groups (HRs ranged from 0.7-1.1). More than five years of abatacept exposure showed a non-significantly increased HR compared with TNFi (HR 1.41, 95% confidence intervals CI 0.74-2.71). For hematological cancers, rituximab treatment showed non-significantly reduced HRs: vs TNFi (HR 0.09; 95%CI 0.00-2.06) and bDMARD-naïve (HR 0.13; 95%CI 0.00-1.89). CONCLUSION: Treatment with tocilizumab/sarilumab, abatacept, or rituximab in RA patients was not associated with increased risks of cancer compared with TNFi-treated and with bDMARD-naïve RA patients in a real-world setting.

Effect of Anti-Interleukin-6 Agents on Psychopathology in a Sample of Patients with Post-COVID-19 Syndrome: An Observational Study.

Interleukin 6 (IL-6) receptor inhibitors tocilizumab and sarilumab have recently been approved for severe coronavirus disease 2019 (COVID-19). They also affect mood, even though their effect on the post-COVID-19 syndrome-related psychopathology still has to be investigated. The aim of this study was to investigate their effect on psychopathology in a sample of patients with post-COVID-19 syndrome. We included 246 patients (34% female, 66% male) aged 18-75 years who had been hospitalized for COVID. Patients were split into those who received anti-IL-6 receptor agents (Anti-IL-6-R, N = 88) and those who did not (Ctrl, N = 158). The former group was further split into those receiving tocilizumab (TOC, N = 67) and those receiving sarilumab (SAR, N = 21). Groups were compared based on clinical characteristics before and during COVID-19 as well as on physical and psychiatric symptoms after COVID-19. Ctrl had less psychiatric and physical symptoms during hospitalization and more post-COVID-19 diarrhea, headache, cough, and dyspnea upon exertion than those receiving IL-6-receptor inhibitors. Ctrl also showed greater difficulties in emotion regulation. These differences were driven by TOC vs. Ctrl, whereas differences between SAR and Ctrl or TOC did not reach significance. IL-6 receptor inhibitors are related to a lower post-COVID-19 illness burden and seem to be effective in emotion regulation. Further research is needed to confirm these findings.

Effectiveness and safety of sarilumab in patients with rheumatoid arthritis: A multicenter, retrospective, inverse probability of treatment-weighted analysis based on the FRAB-registry.

OBJECTIVE: The efficacy and safety of sarilumab (SARI) were investigated in real-world clinical practice in Japan. METHOD: Subjects were 121 rheumatoid arthritis (RA) patients in 23 medical institutions in Fukuoka Prefecture, Japan, who started treatment with SARI between May 2018 and November 2021. Data on the SARI starting dose, patients' baseline characteristics, disease activity, and blood test data at the start of treatment, as well as follow-up data on the SARI dose, disease activity, and adverse events until Week 52. Safety and the continuation rate calculated by the Kaplan-Meier method were evaluated, and the effectiveness of treatment at 1 year was assessed using the clinical disease activity index (CDAI). Patients' baseline characteristics for which significant differences were evident were adjusted with a propensity score by using the inverse probability of treatment-weighting (IPTW) method. RESULTS: The continuation rate at Week 52 was 66.1%. The CDAI showed significant improvement from Week 4 that was maintained until Week 52. Comparisons conducted after IPTW adjustment for patients' baseline characteristics for which significant differences were evident revealed no significant differences at Week 52 between the groups classified by higher or lower body mass index (BMI) (p = 0.231), serious comorbidities (p = 0.973), MTX use (p = 0.321), or prior treatment with ≤ 1 or ≥ 2 biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (p = 0.765). CONCLUSIONS: The results showed that the efficacy of SARI is not affected by BMI, comorbidities, MTX use, or the number of prior b/tsDMARDs, and no new safety concerns were apparent. Key Points • This is the first real-world clinical study to report on the efficacy and safety of SARI in Japan. The results of this study indicate that the efficacy of SARI was not affected by BMI, comorbidities, MTX use, or number of previous b/tsDMARDs. • It was shown that SARI can be used in a Japanese population without any new side effects.

Risk factors for thromboembolic events in patients hospitalized for COVID-19 pneumonia in a general ward and requiring treatment with oxygen.

PURPOSE: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy. METHODS: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events. RESULTS: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage. CONCLUSION: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered.

Safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatments: An interim analysis of a post-marketing surveillance.

OBJECTIVES: An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment. METHODS: The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety. RESULTS: In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections. CONCLUSIONS: Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal.

Comparison of the efficacy and safety of tocilizumab, sarilumab, and olokizumab in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study compared the relative efficacy and safety of olokizumab, tocilizumab, and sarilumab in rheumatoid arthritis (RA) patients who were intolerant or responding inadequately to methotrexate (MTX). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab, tocilizumab, and sarilumab in RA patients who were intolerant or responding inadequately to MTX. RESULTS: Six RCTs comprising 4439 patients met the inclusion criteria. Tocilizumab, sarilumab, olokizumab, and adalimumab treatments achieved a significant American College of Rheumatology 20% (ACR20) response rate compared with placebo. However, tocilizumab was associated with the most favorable surface area using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that tocilizumab treatment had the highest probability of providing the best ACR20 response rate, followed by sarilumab, olokizumab every 2 weeks (Q2W), olokizumab Q4W, adalimumab 40 mg, and placebo. The ACR50 and 70 response rates showed a distribution pattern similar to that of the ACR20 response rate. However, olokizumab Q4W had a higher ranking probability than olokizumab Q2W. The SUCRA rating showed that the placebo was the best intervention with the least adverse events (AEs) and withdrawal due to AEs, followed by interleukin­6 inhibitors. CONCLUSION: Tocilizumab, sarilumab, and olokizumab are more effective than adalimumab and have similar efficacy and safety in RA patients with inadequate responses to MTX.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Biological therapy in polymyalgia rheumatica.

INTRODUCTION: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease of the elderly, treated mainly with systemic corticosteroids. The frequency of side effects of steroids is high in this aged population and increased due to comorbidities. The use of biological treatments could be of interest in this condition. AREAS COVERED: This review takes into account literature data from the PubMed and clinical trial databases concerning the results of the use of biological treatments in PMR, in terms of efficacy and safety of these treatments. EXPERT OPINION: Current data do not allow us to identify any particular efficacy of the various anti-TNF agents used in the treatment of PMR. Anti-interleukin 6 agents (tocilizumab, sarilumab) have shown consistent efficacy results, suggesting a particularly interesting steroid-sparing effect in the population under consideration. The safety profile appears acceptable. Other biologic targeted treatments are currently being evaluated. Anti-interleukin-6 agents may well have a place in the therapeutic strategy for PMR, particularly for patients with steroid-resistant disease or at high risk of complications of corticosteroid therapy.

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarilumab in patients with giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. METHODS: This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. RESULTS: Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80-100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. CONCLUSIONS: Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03600805. Registered on July 26, 2018.

Safety and Outcomes With Combination Therapy With Sarilumab and Baricitinib for Severe COVID-19 Respiratory Infection in Cancer Patients.

OBJECTIVES: This study aims to describe the clinical outcomes of combination therapy with sarilumab and baricitinib for severe novel Coronavirus-19 (COVID-19) infection in cancer patients. With this study, we aim to evaluate the role of expanded immunotherapy for severely ill patients with COVID-19 respiratory infections with limited options. The secondary objective is to assess the safety of combination therapy with sarilumab and baricitinib for severe COVID-19 infection. METHODS: This was a retrospective cohort study of patients admitted to Moffitt Cancer Center with COVID-19 infection between January 2020 and April 2022. Our research received a waiver to sign consent by the patients according to our institutional IRB because it was free of any risk for the patients and respected the patient's privacy. Following the Institutional IRB approval and relevant Equator guidelines, we collected information on patients with severe COVID-19 infection and received sarilumab and baricitinib. We evaluated the survival rate and safety of combination therapy. All the patient's information was de-identified to protect their information according to Health Insurance Portability and Accountability Act (HIPAA). RESULTS: Four patients were included in the data analysis. Two survived, and two of them died (Table 1). All the patients that survived were previously vaccinated. Among the two patients who died, one was vaccinated, and the other was unvaccinated. All the patients tolerated the combination therapy well, and none of the patients who survived developed secondary infections or COVID-19-associated complications beyond 12 months of discharge. CONCLUSION: Our study explores the potential safe combination use of different immune modulators targeting multiple pathways of the inflammatory cascade for severe and refractory COVID-19 respiratory infections in high-risk oncology patients. The small number of patients in our observational study was a limitation. A larger sample of patients will be needed to conclude more precisely the efficacy of the combination therapy of sarilumab and baricitinib for refractory cases of severe COVID-19 respiratory infection. Moreover, exploring other cytokine release signaling pathway targets may be the key to significantly reducing inflammation and further pulmonary fibrosis with chronic unbearable respiratory sequela.

Effect of sarilumab on unacceptable pain and inflammation control in Japanese patients with moderately-to-severely active rheumatoid arthritis: Post hoc analysis of a Phase III study (KAKEHASI).

OBJECTIVE: The aim of this study is to investigate the effects of sarilumab on unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and inflammation in patients with moderately-to-severely active rheumatoid arthritis. METHODS: In this post hoc analysis of the KAKEHASI study, 243 patients received methotrexate with sarilumab 150 or 200 mg or placebo every other week, over 52 weeks. The proportion of patients with UP and correlations of changes in pain VAS from baseline with uncontrolled inflammation (C-reactive protein ≥1 mg/dl) and disease activity indices were assessed. RESULTS: Almost 80% of patients (192/243) had UP at baseline, including ∼60% of patients with uncontrolled inflammation. Among patients receiving sarilumab, inflammation decreased rapidly, with 90% of patients achieving controlled inflammation by Week 2, while 63.1% continued to have UP. The proportion of patients with UP further decreased by Week 16 (28.5%, sarilumab vs. 64.0%, placebo). By Week 52, only ∼10% of patients had UP. Changes in pain VAS correlated with most disease activity indices and patient-reported outcomes. However, marked correlations between changes in pain VAS and C-reactive protein were observed only at Week 16. CONCLUSION: Sarilumab treatment reduced UP and inflammation in Japanese patients with rheumatoid arthritis.