Successful treatment of granulomatosis with polyangiitis using tocilizumab combined with glucocorticoids:A case report

BACKGROUND Tocilizumab is a humanized monoclonal antibody against the interleukin-6(IL-6)receptor that is commonly used to treat large vessel vasculitis and antineutrophil cytoplasmic antibody-related small vessel vasculitis.However,tocilizumab in combination with glucocorticoids for successfully treating granulomatosis with polyangiitis(GPA)has rarely been reported.CASE SUMMARY Here,we report a 40-year-old male patient who suffered GPA for 4 years.He was treated with multiple rounds of drugs,including cyclophosphamide,Tripterygium wilfordii,mycophenolate mofetil,and belimumab,with no improvement.In addition,he exhibited persistently high IL-6 levels.After tocilizumab treatment,his symptoms improved,and his inflammatory marker levels returned to normal.CONCLUSION Tocilizumab may be effective for treating GPA.

Successful treatment of a case of COVID-19 pneumonia following kidney transplantation using paxlovid and tocilizumab

BACKGROUND Since its initial detection in 2019,coronavirus disease 2019(COVID-19)pneumonia has rapidly spread throughout the world in a global pandemic.However,reports of COVID-19 pneumonia among patients following kidney transplantation have been limited and no uniform treatment guidelines for these patients have yet to be established.CASE SUMMARY Here,we report the case of a 39-year-old patient recovering from kidney transplantation who contracted perioperative COVID-19 pneumonia that was successfully controlled with oral paxlovid and a single intravenous drip infusion of tocilizumab following the discontinuation of immunosuppressive drugs.CONCLUSION Given the rapid spread of severe acute respiratory syndrome coronavirus 2 infections,clinicians should be aware of the potential for more cases of COVID-19 among patients following kidney transplantation and be familiar with appropriate treatment options and likely clinical outcomes.

Tocilizumab对肺动脉高压大鼠IL-6及survivin的影响

目的观察tocilizumab对肺动脉高压大鼠白细胞介素-6(IL-6)和survivin的表达水平的影响。方法通过腹腔注射野百合碱诱导建立肺动脉高压大鼠模型,观察tocilizumab对肺动脉高压大鼠IL-6和survivin的表达水平的影响。结果 Tocilizumab干预组大鼠和空白对照组大鼠mPAP、IL-6和survivin含量明显低于实验对照组,P<0.05。Tocilizumab干预组肺动脉血管内膜轻度水肿,血管壁轻度增厚。IL-6和survivin在实验对照组大鼠肺组织和血清中表达强烈,在tocilizumab干预组大鼠肺组织少量表达,而空白对照组大鼠肺组织不表达。结论 Tocilizumab可有效抑制野百合碱可诱导肺动脉高压大鼠IL-6和survivin的表达,抑制肺动脉高压的发生。

抗类风湿关节炎药——Tocilizumab

美国食品药品管理局(FDA)批准Tocilizumab用于治疗类风湿性关节炎,该药适用于使用其他已获批的治疗药物无效的成年中重度类风湿性关节炎患者。Tocilizumab通过抑制白细胞介素-6受体的活性而发挥作用。基于其临床研究显示的严重安全性问题,Tocilizumab仅被推荐用于其他治疗无效的患者。在进行的对类风湿性关节炎成年患者治疗的临床试验中显示Tocilizumab的有效性和安全性。该文通过检索国外文献,对Tocilizumab药理学、药动学、临床试验、不良反应及药物相互作用等进行论述。

Protective function of tocilizumab in human cardiac myocytes ischemia reperfusion injury

Objective:To investigate the protective function of tocilizumab in human cardiac myocytes ischemia-reperfusion injury.Methods:The human cardiac myocytes were treated by tocilizumab with different concentrations(1.0 mg/mL,3.0 mg/mL,5.0 mg/mL) for 24 h.then cells were cultured in ischemia environment for 24 h and reperfusion environment for 1 h.The MTT and flow cytometry were used to detect the proliferation and apoptosis of human cardiac myocytes,respectively.The mRNA and protein expressions of Bcl-2 and Bax were measured by qRT-PCR and western blot,respectively.Results:Compared to the negative group,pretreated by tocilizumab could significantly enhance the proliferation viability and suppress apoptosis of human cardiac myocytes after suffering ischemia reperfusion injury(P<0.05).The expression of Bcl-2 in tocilizumab treated group were higher than NC group(P<0.05).while the Bax expression were lower(P<0.05).Conclusions:Tocilizumab could significantly inhibit apoptosis and keep the proliferation viability of human cardiac myocytes after suffering ischemia reperfusion injury.Tocilizumab may obtain a widely application in the protection of ischemia reperfusion injury.

Tocilizumab promotes corneal allograft survival in rats by modulating Treg-Th17 balance

AIM: To examine the therapeutic effects of tocilizumab on experimental corneal transplantation and its effect on Treg/Th17 balance. METHODS: Allograft corneal graft was performed between host Sprague Dawley and Wistar donor rats.The rats were randomly divided into four groups: normal,autograft, allograft, and allograft treated with tocilizumab.Kaplan-Meier was performed to draw the survival curve.The protein levels of interleukin-17A(IL-17A), vascular endothelial growth factor(VEGF), and forkhead box protein3(Foxp3) were measured by immunohistochemistry.The mRNA levels of IL-17A, VEGF, retinoid-related orphan receptor gammat(RORγt), interleukin-6(IL-6) and Foxp3 were detected by reverse transcription real-time polymerase chain reaction(RT-PCR). The Treg and Th17 cells were investigated by flow cytometry. RESULTS: The survival time of tocilizumab group was(24±1.27 d) longer than that of allograft group(10±0.55 d).Moreover, immunohistochemical examination revealed that IL-17A and VEGF protein levels in the allograft group were significantly higher than that of tocilizumab group(P<0.01),while Foxp3 levels in the allograft group was significantly lower than that of the tocilizumab treated group(P<0.001).Flow cytometry showed that the number of Th17 cellsin allograft group was significantly higher than that in tocilizumab group(P<0.001). Meanwhile, the number of Tregs was significantly lower than in tocilizumab group(P<0.001). Simultaneously, Foxp3 m RNA expression level in corneal tissues of tocilizumab treated group was significantly higher than other groups(P<0.001). CONCLUSION: These findings suggest that tocilizumab may promote corneal allograft survival, possibly by modulating Treg-Th17 balance.

Use of subcutaneous tocilizumab to prepare intravenous solutions for COVID-19 emergency shortage:Comparative analytical study of physicochemical quality attributes

COVID-19,a disease caused by the novel coronavirus SARS-Co V-2,has produced a serious emergency for global public health,placing enormous stress on national health systems in many countries.Several studies suggest that cytokine storms(interleukins)may play an important role in severe cases of COVID-19.Neutralizing key inflammatory factors in cytokine release syndrome(CRS)could therefore be of great value in reducing the mortality rate.Tocilizumab(TCZ)in its intravenous(IV)form of administration-Ro Actemra?20 mg/m L(Roche)-is indicated for treatment of severe CRS patients.Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe,with several ongoing clinical trials.This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals,which has resulted in drug shortages.Here,we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion,at 6 mg/m L and 4 mg/m L,prepared from Ro Actemra?20 mg/m L(IV form)and from Ro Actemra?162 mg(0.9 m L solution pre-filled syringe,subcutaneous(SC)form),to evaluate the use of the latter for preparing clinical solutions required for IV administration,so that in a situation of shortage of the IV medicine,the SC form could be used to prepare the solutions for IV delivery of TCZ.It is important to remember that during the current pandemic all the medicines are used off-label,since none of them has yet been approved for the treatment of COVID-19.

Clinical efficacy of tocilizumab treatment in severe and critical COVID-19 patients

BACKGROUND The main pathophysiological basis of coronavirus disease 2019(COVID-19)causing respiratory failure is a cytokine storm and interleukin-6(IL-6)is an important component of the COVID-19 cytokine storm.As a specific antagonist of IL-6,tocilizumab may block the cytokine storm of COVID-19.The Diagnosis and Treatment Guidelines of New Coronavirus Pneumonia(7 th Edition)includes tocilizumab as a recommended drug for immunotherapy in severe and critical COVID-19 patients.However,the specific clinical efficacy of tocilizumab in the treatment of COVID-19 patients is worth studying.AIM To determine the clinical efficacy of tocilizumab in inhibiting the cytokine storm in COVID-19.METHODS In total,19 severe and critical COVID-19 patients were enrolled in this study,and were treated with tocilizumab in Optical Valley Campus of Hubei Maternal and Child Health Care Hospital from February 20 to March 31,2020.The imaging manifestations and clinical data before and after treatment were analyzed retrospectively,including routine peripheral venous blood tests,routine blood biochemical tests,coagulation test,C-reactive protein(CRP),IL-6,and arterial blood gas analysis.RESULTS Of the 19 patients in this group,13(68.4%)had significantly improved symptoms of COVID-19(5 patients were discharged directly and 8 patients were transferred after improvement)following treatment.One case was invalid,1 case was exacerbated,and 4 deaths(21.1%)were observed(all critical cases).The lymphocyte count,CRP,lactic acid,oxygenation index,fibrinogen(FIB)and IL-6 levels were significantly different in the improved group.CONCLUSION Tocilizumab treatment is effective against IL-6 in COVID-19 patients,but it does not completely inhibit the inflammation and cytokine storm in all patients with COVID-19.In the clinical treatment of COVID-19 patients,attention should be paid to the timing of drug administration and other adjuvant treatments.

Idiopathic multicentric Castleman disease with pulmonary and cutaneous lesions treated with tocilizumab:A case report

BACKGROUND Human herpes virus-8(HHV-8)-negative,idiopathic multicentric Castleman disease(iMCD)is a rare and life-threatening disorder driven by proinflammatory cytokines,which is still poorly understood.Pulmonary parenchyma lesion is a rare condition in iMCD,which mainly manifests as lymphocytic interstitial pneumonia and is an indicator of severe iMCD.Cutaneous lesion is also very rare and mainly occurs in Asians.There have been few reports of iMCD patients with both skin and lung parenchyma involvement.CASE SUMMARY We present a Chinese man who complained about a 3-year history of intermittent dry cough and a 2-year history of diffuse reddish-brown maculopapules.Laboratory examination revealed polyclonal hypergammaglobulinemia and hypercytokinemia including interleukin 6.Chest computed tomography revealed small patchy shadows with ground-glass nodules scattered in two lobes and mediastinal lymphadenopathy.The pathological result of the lymph node was consistent with the plasma cell type of Castleman disease.As serum human immunodeficiency virus test and HHV-8 staining of the lymph node were negative,the patient was finally diagnosed with HHV-8 negative i MCD.He was treated with tocilizumab at an intravenous(i.v.)dose of 8 mg/kg every 2 wk combined with methylprednisolone at an i.v.dose of 80 mg/d initially with gradual dose tapering.Partial remission was achieved 9 mo later.CONCLUSION i MCD with lung parenchyma and skin involvement is a rare condition that requires clinicians'attention and awareness for early diagnosis.

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

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

Tocilizumab Significantly Decreases Reactive Oxygen Species Level in Patients with Rheumatoid Arthritis

To determine the effect of tocilizumab (TCZ) on reactive oxygen species (ROS) in 11 patients with rheumatoid arthritis (RA), reactive oxygen metabolites (d-ROM) were measured using a Free Radical Elective Evaluator. The Disease Activity Score (DAS28) and matrix metalloproteinase-3 (MMP-3) level were also evaluated. d-ROM measured 392 ± 110 Carratelli units [U. CARR] on initiation of TCZ, and significantly decreased to 237 ± 82, 248 ± 88, and 226 ± 91 U.CARR after 3, 6, and 12 months, respectively

Effect of pulsed corticosteroids and tocilizumab on hyperinflammation in COVID-19 patients with acute respiratory distress syndrome

Objective:To compare the efficacy of pulsed-dose corticosteroids(≥250 mg methylprednisolone,3 days)and tocilizumab in treating COVID-19-related hyperinflammation.Methods:This prospective observational study included RT-PCR positive COVID-19 patients with acute respiratory distress syndrome,who were admitted to the COVID-19 Adult Intensive Care Unit of Prof Dr.Murat Dilmener Emergency Hospital(Istanbul,Turkey)between December 1,2020 and February 28,2021.Clinical,laboratory and radiological examinations were used to diagnose COVID-19 associated hyperinflammation.Three cohort groups were formed:the pulsed-dose corticosteroids group(250 mg methylprednisolone for 3 days),the tocilizumab group(8 mg/day single dose or 400 mg/day for 2 days),and the combined group(pulsed-dose corticosteroid+tocilizumab).The difference in mortality rates among the groups was compared primarily.The most common cause(s)of death was determined.Furthermore,adverse events(secondary infection,acute kidney injury,arrhythmia,gastrointestinal system bleeding)for 28 days were recorded.Results:A total of 60 patients were included in this study,with 20 patients in each group.There was no statistically significant difference between the 3 groups in mortality rates(55%in the pulsed corticosteroid group,60%in the tocilizumab group,50%in the combined group,χ2=0.404,P=0.817).Infectious causes were found to be the most common cause of mortality in all the three groups,and no difference was found between them(χ2=0.404,P=0.817).There was also no difference in the development of adverse events such as secondary infection,acute kidney injury,arrhythmia,and gastrointestinal bleeding among the groups(P>0.05).Conclusions:Corticosteroids can be used instead of tocilizumab to treat hyperinflammation in COVID-19 patients with acute respiratory distress syndrome.

Tocilizumab as treatment for COVID-19:A systematic review and meta-analysis

BACKGROUNDThe majority of patients with coronavirus disease 2019 (COVID-19) have goodprognoses, but some develop a critical illness that can lead to death. Evidenceshows severe acute respiratory syndrome is closely related to the inducedcytokine storm. Interleukin-6 is a key player;its role in systemic inflammation iswell known.AIMTo evaluate the effect of tocilizumab (TCZ), an interleukin-6 receptor antagonist,on the outcomes for patients with COVID-19 pneumonia.METHODSPubMed, EMBASE, SCOPUS, Web of Science, MedRxiv, Science Direct, and theCochrane Library were searched from inception to 9th June 2020 for observationalor prospective studies reporting results of hospitalized adult patients withCOVID-19 infection treated with TCZ. Effect sizes were reported as odds ratios(ORs) with 95% confidence intervals (CIs), and an OR less than 1 was associatedwith a better outcome in those treated with TCZ.RESULTSOverall 13476 patients (33 studies;n = 3264 received TCZ) with COVID-19pneumonia and various degree of severity were included. Outcome wasimproved with TCZ. In the primary analysis (n = 19 studies reporting data),mortality was reduced in patients treated with TCZ (OR = 0.64, 95%CI: 0.47-0.87;P < 0.01). In 9 studies where risk of death with TCZ use was controlled for othervariables mortality was reduced by 57% (OR = 0.43, 95%CI: 0.27-0.7;P < 0.01).Intensive care need (mechanical ventilation) was also reduced (OR = 0.36, 95%CI:0.14-0.89;P = 0.02).CONCLUSIONIn COVID-19-infected patients treated with TCZ, outcome may be improvedcompared to those not treated with TCZ.

Remission of arthritis but persistent cutaneous lesions following tocilizumab treatment in a RA-patient suffering from concomitant psoriasis

Modulation of the interleukin-6 pathway with tocilizumab has been demonstrated to be highly effective in substantial numbers of patients suffering from rheumatoid arthritis (RA), and juvenile idiopathic arthritis. A pivotal role of the IL-6 pathway has been also established in other autoimmune conditions including psoriasis and psoriatic arthritis, becoming attractive targets for therapeutic IL-6 inhibition. Here, we describe the first case of tocilizumab treatment in a RA-patient suffering from concomitant severe psoriasis, who achieved remission of RA, whereas no improvement of psoriatic lesions could be observed.

Clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis

Objective:To study the clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis.Methods:114 patients with rheumatoid arthritis admitted from May 2015 to April 2018 were randomly divided into control group(n=57)and observation group(n=57).The control group was treated with leflunomide.On the basis of this,the observation group was treated with tocilizumab for 12 weeks.Functional indicators,erythrocyte sedimentation rate(ESR),rheumatoid factor and inflammatory factors were evaluated and adverse reactions were recorded.Results:The total treatment efficiency of the observation group(89.47%)was significantly higher than that of the control group(75.44%)(P<0.05).Morning stiffness time,joint pain score,joint swelling score,ESR,serum C-reactive protein(CRP),rheumatoid factor(RF),tumor necrosis factor(TNF-α),and interleukin-1 were observed in the observation group and the control group.The levels of IL-1),IL-6,IL-8 and other indicators were lower than those before treatment.The indexes of the observation group were significantly lower than those before treatment(P<0.05),and after treatment The morning stiffness time,joint pain score,joint swelling score,ESR,CRP,RF,TNF-α,IL-1,IL-6,IL-8 and other indicators in the observation group were significantly lower than those in the control group(P<0.05).The incidence of adverse reactions in the observation group was 14%,and the incidence of adverse reactions in the control group was 17.54%.Toltuzumab combined with leflunomide in the treatment of rheumatoid arthritis did not increase the probability of adverse reactions.Conclusion:The use of tocilizumab combined with leflunomide in the treatment of rheumatoid joints has good efficacy and safety.This may be related to a significant reduction in inflammatory factors TNF-α,IL-1,IL-6,IL-8 and the like.

The Efficacy of Tocilizumab for Takayasu Arteritis: Review of the Literatures

Takayasu arteritis is a large vessel vasculitis of the young women with giant cells and granuloma formation. The diagnosis and management of the disease are really not so easy because of the insidious onset and the difficulties in assessment of disease activity. Nearly 60% of the patients are corticosteroid resistant or dependent and relapses are very frequent during taper of the dose [1]. The novel biologic agents as Anti-TNF, Rutiximab and Tocilizumab provide acceptable response rates with low toxicity. Herein, we reviewed the efficacy of Tocilizumab in Takayasu arteritis.

Tocilizumab下调NF-κB/JNK减轻急性肺、肾损伤的效果与对脓毒症小鼠模型存活率的影响

研究分析Tocilizumab通过下调NF-κB/JNK减轻急性肺和肾损伤并提高脓毒症小鼠模型的存活率。方法 本次研究选择同一实验室的48只雄性C57BL/6小鼠作为此次研究对象,随机分成两组,并运用盲肠扎穿孔法(CLP)建立脓毒血症动物模型,视为CLP组,另一只作为假手术(SMAM)组,组间平均分配,每组各24只,根据给药方式不同分为SHAM组和两SHAM+TCZ组、CLP组和两CLP+TCZ,共6小组,每组8只。CLP组小鼠采取结扎盲肠全长,使用无菌针头穿刺3处,SHAM组采取剖腹术。脓毒血症动物模型分为CLP组、CLP+TCZ (Tocilizumab注射4 mg/kg)、CLP+TCZ (Tocilizumab注射8mg/kg) 。假手术组:SHAM组、SHAM+TCZ (Tocilizumab注射4 mg/kg) 组、CLP+TCZ (Tocilizumab注射8mg/kg)。观察6小组急性肺和肾损伤情况以及小鼠模型的存活率。结果 CLP+TCZ (8mg/kg)W/D、肺损伤评分均优于其他组别,(P<0.05)视为差异具有统计学意义。 CLP+TCZ (8mg/kg)血清肌酐、血尿素氮肾功能指标均优于其他组别,(P<0.05)视为差异具有统计学意义。CLP+TCZ (8mg/kg)IL-6、IL-Iβ、TNF-α炎性因子水平均优于其他组别,(P<0.05)视为差异具有统计学意义。Tocilizumab治疗可明显提高脓毒症小鼠的存活率,(P<0.05)视为差异具有统计学意义。结论 Tocilizumab通过下调NF-κB/JNK可减轻急性肺和神损伤并且可提高脓毒血症小鼠模型的存活率,为脓毒血症的治疗以及药物研发提供研究基础。

托珠单抗联合泼尼松和甲氨蝶呤治疗难治性中重度类风湿关节炎临床评价

目的探讨托珠单抗联合泼尼松、甲氨蝶呤治疗难治性中重度类风湿关节炎(RA)的临床疗效。方法选取医院2020年3月至2022年3月收治的难治性中重度RA患者145例,采用分层随机法分为观察组(72例)和对照组(73例)。两组患者均口服醋酸泼尼松片、甲氨蝶呤片,观察组患者加用托珠单抗注射液静脉滴注。两组均连续治疗3个月。结果治疗后,两组患者的关节疼痛评分、肿胀评分均显著降低,晨僵持续时间均显著缩短,疾病活动指数28量表评分均显著降低,Fugl-Meyer运动功能评价量表评分均显著升高,类风湿因子、C反应蛋白水平及红细胞沉降率均显著降低,基质金属蛋白酶-3水平均显著降低,金属蛋白酶组织抑制因子-1水平均显著升高(P<0.05);且观察组患者上述指标改善程度均更显著(P<0.05)。观察组与对照组不良反应发生率相当(11.11%比8.22%,P>0.05)。结论托珠单抗联合泼尼松、甲氨蝶呤治疗难治性中重度RA,可有效缓解患者的关节炎性症状,降低血清炎性指标水平,改善关节活动能力和关节损伤。