To evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan.
Paediatric patients with sJIA ...initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks.
Of 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (<0.3 mg/dL), respectively.
These first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study.
Abstract
Objective
To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).
Methods
Patients completing the randomized, ...double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety.
Results
All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference –0.120 mg/kg/day; 95% CI −0.154, −0.087). Imaging evaluations indicated that most patients’ disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported.
Conclusion
These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns.
Trial registration
JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.
The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, ...this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.
Objective To evaluate infliximab (IFX) in patients with Kawasaki disease (KD) that was unresponsive to additional intravenous immunoglobulin (IVIG) therapy and subsequent rescue with supplementary ...plasma exchange (PE) in patients unresponsive to treatment. Study design We studied 76 patients with KD who received IVIG therapy twice and were unresponsive to additional IVIG. Reults Seventy were treated with IFX alone (92.1%). Six patients who were unresponsive IFX (7.9%) were further treated by PE. This resulted in disappearance of fever and other clinical symptoms, and improvement of laboratory data. There was no severe life-threatening adverse events.Twelve of the 76 cases had developed coronary artery dilatation, and 3 had coronary artery aneurysm within 1 month of disease onset. At the end of follow-up, in all cases, coronary artery lesions were suppressed or reversed. Conclusions Treatment of intractable KD with sequential IVIG, IFX, and PE treatments in a step-wise protocol was effective.
Summary Background Systemic-onset juvenile idiopathic arthritis does not always respond to available treatments, including antitumour necrosis factor agents. We investigated the efficacy and safety ...of tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, in children with this disorder. Methods 56 children (aged 2–19 years) with disease refractory to conventional treatment were given three doses of tocilizumab 8 mg/kg every 2 weeks during a 6-week open-label lead-in phase. Patients achieving an American College of Rheumatology Pediatric (ACR Pedi) 30 response and a C-reactive protein concentration (CRP) of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks or until withdrawal for rescue medication in a double-blind phase. The primary endpoint of the double-blind phase was an ACR Pedi 30 response and CRP concentration of less than 15 mg/L. Patients responding to tocilizumab and needing further treatment were enrolled in an open-label extension phase for at least 48 weeks. The analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , numbers NCT00144599 (for the open-label lead-in and double-blind phases) and NCT00144612 (for the open-label extension phase). Findings At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and 38 (68%) patients, respectively. 43 patients continued to the double-blind phase and were included in the efficacy analysis. Four (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L compared with 16 (80%) of 20 in the tocilizumab group (p<0·0001). By week 48 of the open-label extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%), and 43 (90%) of 48 patients, respectively. Serious adverse events were anaphylactoid reaction, gastrointestinal haemorrhage, bronchitis, and gastroenteritis. Interpretation Tocilizumab is effective in children with systemic-onset juvenile idiopathic arthritis. It might therefore be a suitable treatment in the control of this disorder, which has so far been difficult to manage. Funding Chugai Pharmaceuticals.
Systemic juvenile idiopathic arthritis (SJIA), a subtype of juvenile idiopathic arthritis, is characterized by systemic features, such as spiking fever, salmon-colored macular rash, serositis, ...lymphadenopathy, hepatosplenomegaly, and joint inflammation. It is also often complicated with growth retardation, osteoporosis, and sometimes macrophage activation syndrome (MAS) develops, a potentially fatal disease. Pathogenesis of SJIA and MAS is not yet fully understood, but activation of the innate immune system, which causes phagocytosis by dendritic cells, monocytes, and macrophages to produce proinflammatory cytokines such as interleukin-6 (IL-6), IL-1β and IL-18, is thought to be a primary abnormality associated with SJIA. Dysregulated production of IL-6 plays a major role in the development of systemic clinical features. The blockade of IL-6 might thus represent a novel strategy for the treatment of SJIA. Several phase II and III clinical trials of a humanized anti-IL-6 receptor antibody, tocilizumab, proved its outstanding efficacy and tolerable safety profile for SJIA refractory to conventional treatment regimens. This resulted in the approval of tocilizumab for the treatment of SJIA in Japan, India, the EU and the USA.
Abstract Human parechovirus-3 (HPeV-3) has been reported to cause a sepsis-like illness in neonates and young infants. We experienced the occurrence of HPeV-3 infection in nine neonates and young ...infants (eight boys, one girl; aged 14–52 days, median 31 days). They were admitted to our hospital with the chief complaints of fever persisting for 3–5 days (median 4 days) and lethargy. Five infants presented with abdominal distension and six had a rash (including acral reddening), as was previously reported with this viral infection. Abdominal distension with navel protrusion and acral reddening during the course were characteristic. Laboratory data were characterized by elevated values for serum AST, LDH, FDP, D-dimer, ferritin, soluble IL-2 receptor, triglyceride, choline esterase, and urinary β2 -microglobulin. Two of our nine patients presented with a hemophagocytic lymphohistiocytosis (HLH)-like illness and required specific therapy. These data suggest that HPeV-3 is an important virus that can cause hypercytokinemia, which sometimes leads to HLH, and systemic inflammatory response syndrome in neonates and young infants.
To assess the efficacy and safety of canakinumab in Japanese patients with systemic juvenile idiopathic arthritis (sJIA).
This was an open-label, single-arm active treatment study. sJIA patients, ...aged ≥2 to <20 years, were administered canakinumab 4 mg/kg every 4 weeks for ≤48 weeks. The co-primary endpoints were the proportion of patients who achieved an adapted American College of Rheumatology pediatric (ACR pedi) 30 criteria at week 8, and the proportion of patients who successfully tapered corticosteroids at week 28. Herein, the efficacy and safety results up to 48 weeks are reported.
Of the 19 patients enrolled, 15 (78.9%) had previously used tocilizumab. All patients achieved ACR pedi 30 at week 8 and 73.7% (14/19) successfully tapered corticosteroids at week 28. At week 48, ACR pedi 50/70/90/100 responses were achieved by 100.0%/100.0%/87.5%/68.8% of patients. The most common adverse events (AEs) were infections (271.6 patient-years), 42.1% (8/19) patients had serious AEs. Two potential cases of macrophage activation syndrome were identified. No deaths were reported.
Canakinumab was efficacious in Japanese patients with sJIA and was associated with substantial corticosteroid dose reduction in the majority of patients. The safety profile of canakinumab was consistent with that observed from previous studies.
NCT02396212).
Background: The treatment of Kawasaki disease patients who fail to respond to initial i.v. immunoglobulin (IVIG) therapy is controversial. The aim of the present study was to investigate the ...long‐term efficacy of plasma exchange (PE) treatment for refractory Kawasaki disease.
Methods: A total of 125 Kawasaki disease patients refractory to IVIG were treated with PE. Coronary artery lesions (CAL) before PE, in the acute period, and during the late period were examined retrospectively.
Results: Residual sequelae requiring medical treatment occurred in six cases in the late period. The outcomes of treatment tended to be better when PE was begun in the early stage. Sequelae remained in 2.8% of patients in whom PE was initiated prior to day 9 after onset, and were present in 15% of patients in whom PE was started on or after day 10. The 105 patients whose coronary arteries were normal before PE had no sequelae (residual sequelae: 0%). Dilatation was present before PE in 14 patients, but remained in only two patients in the late period (residual sequelae, 14.3%). In four of the six patients in whom aneurysms had already formed before PE, the lesions had advanced into giant aneurysms, but in the other two patients they returned to the normal range (residual sequelae, 66.6%).
Conclusions: The outcomes of PE for Kawasaki disease refractory to IVIG are favorable, and the effectiveness of this treatment is excellent, particularly if it is initiated before CAL arise.
We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab ...every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
PDF
