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Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial
Abstract
Background:
Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy. Tocilizumab--an inhibitor of interleukin 6 receptor signalling--has been studied as monotherapy in several clinical trials. We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis.
Methods:
We did this randomised, double-blind, parallel-group, phase 4 superiority study in 76 centres in 15 countries in North and South America, Australasia, and Europe. We enrolled patients who were aged at least 18 years, had severe rheumatoid arthritis for 6 months or more, and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment. Patients were randomly assigned (1:1; block size of four) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks. Investigators, patients, and sponsor personnel were masked to assignment. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01119859.
Findings:
We screened 452 patients and enrolled 326 patients. The intention-to-treat population contained 325 patients (163 assigned to tocilizumab, 162 assigned to adalimumab). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group (-3·3) than in the adalimumab group (-1·8) patients (difference -1·5, 95% CI -1·8 to -1·1; p<0·0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts.
Interpretation:
Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate. The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings.
Funding:
F Hoffmann-La Roche.
... The use of IL-6R inhibitors was associated with improvement of composite scores of disease activity as well as with inhibition of structural damage [50][51][52][53]. Both tocilizumab and sarilumab were superior to adalimumab, a TNF antagonist, in the control of inflammatory manifestations when used as monotherapy [54][55][56][57]. More recently, tocilizumab was proven efficacious in the treatment of other inflammatory diseases, including systemic juvenile idiopathic arthritis, adult onset-Still's disease, and giant cell arteritis [58][59][60]. ...
... In RA, thrombocytosis correlates with IL-6 levels and disease activity [92,93]. Of note, platelet count decreases to a greater extent in RA patients treated with tocilizumab compared to adalimumab [54]. In this clinical trial, low grade thrombocytopenia occurred also more frequently in the tocilizumab group compared to adalimumab (9.3% vs 3.1%). ...
... Regarding psychosocial symptoms, the randomized OPTION trial demonstrated a significant improvement of the mental component summary (MCS) score in the tocilizumab group compared to placebo [186]. The superiority of tocilizumab compared to adalimumab on same score was also observed in the ADACTA trial [54]. A cohort study showed improvement of scores reflecting depression (Hamilton Depression Score) and anxiety (Hamilton Anxiety Score) after tocilizumab introduction [187]. ...
Interleukin (IL)-6 is produced locally in response to an inflammatory stimulus, and is able to induce systemic manifestations at distance from the site of inflammation. Its unique signaling mechanism, including classical and trans-signaling pathways, leads to a major expansion in the number of cell types responding to IL-6. This pleiotropic cytokine is a key factor in the pathogenesis of rheumatoid arthritis (RA) and is involved in many extra-articular manifestations that accompany the disease. Thus, IL-6 blockade is associated with various biological effects beyond the joints. In this review, the systemic effects of IL-6 in RA comorbidities and the consequences of its blockade will be discussed, including anemia of chronic disease, cardiovascular risks, bone and muscle functions, and neuro-psychological manifestations.
... According to the searching strategy, 2159 relevant literatures, including 4 RCTs [24][25][26][27] were initially obtained for a total of 2070 patients. The literatures were published from 2013 to 2020 for 5 interventions, with Sirukumab in 2 dose groups and the remaining drugs 1 dose group. ...
... A total of 4 RCTs [24][25][26][27] and 5 interventions were included in this study including 3 two-arm studies and 1 three-arm study. The network was plotted with ACR20, ACR50, and ACR70 indicators, respectively. ...
... Three [24,25,27] reported ACR20 before and after treatment, and 4 [24][25][26][27] reported ACR50 and ACR70 before and after treatment. Four of these drugs (Sarilumab, Sirukumab 50 mg and 100 mg, Adalimumab, Tocilizumab) were not significantly different in reducing ACR20 (P > .05); ...
... On the contrary, other studies suggesting that tocilizumab has higher rate of serious respiratory tract infections than ADA and ETN, like this prospective cohort study conducted in UK [10], which reported that tocilizumab had a higher rate of serious respiratory tract infections than ADA and ETN, but these findings were no longer statistically significant in the fully Orthopedics and Rheumatology Open Access Journal (OROAJ) adjusted model. Tocilizumab had superior efficacy compared with adalimumab suggesting that it may be a more potent drug which could provide a biologically plausible link to a higher infection rate as shown in this RCT [20]. ...
... Another systematic review and meta-analysis [22] concluded that tocilizumab has higher IR of SI 5.45 (4.26, 6.96), than TNFi 4.90 (4.41, 5.44). The same results from ADACTA RCT [20] which compared tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis, it reported that tocilizumab had a higher risk of SI compared with adalimumab, but this difference was not statistically significant. It also founded that tocilizumab had superior efficacy compared with adalimumab suggesting that it may be a more potent drug which could provide a biologically plausible link to a higher infection rate. ...
To assess the risk of serious infections (SI) in rheumatoid arthritis patients receiving biological agents. This retrospective cohort study was conducted at a tertiary hospital in Malaysia. The medical records of RA patients aged ≥18 years and receiving biological agents from January 2010 until August 2018 were included. Each enrolled medical record was traced for up to 1 year starting from date of receiving biologics until an infection took place. A total of 57 patients’ medical records were included in this study. A total of 8 serious infections (Sis) were identified, the most frequent was respiratory tract infection (RTI). The overall incidence rate (IR) of SI was 14 per 100 PYs (person-years): 6.7 per 100 PYs in adalimumab group, 13.6 per 100 PYs in etanercept group, and 20 per 100 PYs in tocilizumab group. There was no significant difference in risk of SI between treatment groups, the adjusted HR (95% CI) for adalimumab was 0.348 (0.039 – 3.118), p=0.346 and for etanercept was 0.669 (0.150 – 2.992), p=0.599 compared with tocilizumab. Only lung diseases was determined as a true predictor in the adjusted model, lung diseases adjusted OR (95% CI) was 7.498 (1.043 – 53.903), p=0.045, but adjusted OR (95% CI) for long term use of steroids was 3.076 (0.42 – 22.543), p=0.269, and for age was 0.875 (0.123 – 6.203), p=0.894. Based on our findings, the incidence of SI was not determined by the type of biological agents. Lung disease was a significant factor associated with the risk of RTI.
... Una limitante para estos estudios es que los hallazgos de laboratorio en un paciente con COVID-19 no están necesariamente correlacionados con el estado clínico del paciente, pues no se ha podido demostrar que el regreso a parámetros normales de los reactantes en fase aguda sea pronóstico certero de mejoría clínica, al igual que a veces se pueden obtener niveles elevados de ferritina aunque el paciente aun no presente manifestaciones clínicas graves 25 . Lo mismo sucede con los estudios imagenológicos, pues las lesiones radiológicas no van al DESARROLLO Hasta la fecha, se han iniciado varios ensayos clínicos independientes a nivel mundial para explorar la eficacia y la seguridad del tocilizumab para el tratamiento del síndrome de liberación de citoquinas en pacientes con COVID-19 19,20,21,22,23,24 . ...
... Se hace necesario seguir profundizando en el estudio de la eficacia del tocilizumab que no solo se emplea en pacientes con COVID-19 sino en otras enfermedades autoinmunitarias antes mencionadas y también en pacientes oncológicos que desarrollan síndrome de liberación de citoquinas como complicación de la inmunoterapia de células T o "inmunoterapia celular adoptiva" 21,22 . Por esto sería útil la realización de futuras investigaciones donde se evalúe el tratamiento con tocilizumab sin terapias concomitantes; al igual que las reacciones adversas vinculadas al uso del medicamento. ...
... Una limitante para estos estudios es que los hallazgos de laboratorio en un paciente con COVID-19 no están necesariamente correlacionados con el estado clínico del paciente, pues no se ha podido demostrar que el regreso a parámetros normales de los reactantes en fase aguda sea pronóstico certero de mejoría clínica, al igual que a veces se pueden obtener niveles elevados de ferritina aunque el paciente aun no presente manifestaciones clínicas graves 25 . Lo mismo sucede con los estudios imagenológicos, pues las lesiones radiológicas no van al DESARROLLO Hasta la fecha, se han iniciado varios ensayos clínicos independientes a nivel mundial para explorar la eficacia y la seguridad del tocilizumab para el tratamiento del síndrome de liberación de citoquinas en pacientes con COVID-19 19,20,21,22,23,24 . ...
... Se hace necesario seguir profundizando en el estudio de la eficacia del tocilizumab que no solo se emplea en pacientes con COVID-19 sino en otras enfermedades autoinmunitarias antes mencionadas y también en pacientes oncológicos que desarrollan síndrome de liberación de citoquinas como complicación de la inmunoterapia de células T o "inmunoterapia celular adoptiva" 21,22 . Por esto sería útil la realización de futuras investigaciones donde se evalúe el tratamiento con tocilizumab sin terapias concomitantes; al igual que las reacciones adversas vinculadas al uso del medicamento. ...
Introducción: tocilizumab, fue aprobado en el 2017 por la Food and Drugs Administration para el tratamiento del síndro- me de liberación de citoquinas, por lo que se ha empleado en la terapéutica de pacientes graves por SARS-CoV 2. Obje- tivo: describir la efectividad del tocilizumab en el tratamiento del síndrome de liberación de citoquinas en pacientes con COVID- 19. Objetivo: describir la efectividad del tocilizumab en el tratamiento del síndrome de liberación de citoquinas en pacientes con COVID- 19. Material y Métodos: se realizó una revisión en el período comprendido entre el 1 de junio al 30 de agosto del 2020 para la cual se empleó la estrategia de búsqueda “coronavirus” OR “COVID-19” OR “SARS-CoV2” AND “tocilizumab” en bases de datos como Pubmed, The Cochrane Library, Medline, LILACS. Se seleccionó un total de 25 referencias bibliográficas. Desarrollo: el uso del tocilizumab se asocia con una mejoría tanto clínica, imagenológica y en los hallazgos de laboratorio de los pacientes enfermos con COVID- 19 que desarrollan el síndrome de liberación de citoquinas. Conclusiones: muchos pacientes con COVID- 19 han recibido tratamiento concomitante con antibióticos, antivirales e hidroxicloroquina previo a la administración de tocilizumab por lo que se necesitan más investigaciones que determinen la efectividad del tocilizumab sin otra terapia concomitante.
... It has been reported that TCZ monotherapy is better than methotrexate monotherapy, and that TCZ monotherapy was more effective than TNF inhibitor monotherapy. 3,4 These reports suggest that TCZ could be an effective option for elderly RA patients in whom it is difficult to use MTX concomitantly. On the other hand, post-marketing surveillance in Japan has shown that old age is a risk factor for serious infections among patients using TCZ. 5 Because the steroid dose is generally higher in elderly RA patients than in younger RA patients, the risk of infection is increased among the elderly patients. ...
... ADACTA study, which was a study conducted outside Japan, demonstrated that TCZ monotherapy was more effective than adalimumab monotherapy. 4 In addition, The ACTRA-RI study demonstrated that there was no significant difference in retentions of TCZ with and without MTX during maintenance therapy for RA patients achieving clinical improvements during the first year. 20 In the present study, both the efficacy and safety of TCZ were not inferior in the elderly RA patients compared with the younger RA patients. ...
Objective: We evaluated the efficacy, safety, and drug survival rate of tocilizumab in the elderly patients with rheumatoid arthritis (RA). Methods: This study was conducted in 108 RA patients who started tocilizumab between 2008 and 2018. The patients were divided into a young group (<65 years) and an elderly group (≥65 years). The efficacy, safety, and drug survival rate of tocilizumab were compared between the two groups. Results: At baseline, there were no significant differences between the elderly ( n = 45) and the young group ( n = 63) in RA duration, percentage of biologic-naïve, and RA disease activity. Health Assessment Questionnaire-Disability Index (HAQ-DI) was higher, renal function was worse, and frequency of using methotrexate was lower in the elderly group. Tocilizumab demonstrated similar efficacy in the elderly and the young group with Clinical Disease Activity Index and HAQ-DI. Compared with baseline, the frequency of steroid use was lower at one year after initiation of tocilizumab in both groups. There was no significant difference between the groups in the drug survival rate of tocilizumab for three years. Discontinuation rates of TCZ due to toxic adverse events were similar between the two groups. Conclusions: The efficacy, steroid-sparing effect, and safety of tocilizumab therapy, as well as the drug survival rate for three years, were not inferior in elderly RA compared to young RA patients.
... Of the 15 studies, all except one [26] compared TCZ with placebo [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. All selected studies except one were randomly assigned to TCZ 8 mg or another comparator were included in the meta-analysis. ...
... Of the 15 studies, all except one [26] compared TCZ with placebo [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. All selected studies except one were randomly assigned to TCZ 8 mg or another comparator were included in the meta-analysis. ...
The present systematic review and meta-analysis was conducted to assess the effect of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). We systematically searched all potential articles in the main databases, including PubMed, Scopus, EMBASE, Web of Sciences (ISI), and Cochrane Center. The search was subsequently updated in December 2020. The initial review and extraction of information were performed independently by two authors to collect the first author and publication year; sample size; mean age of the intervention and control groups; the dose of TCZ, and the follow-up duration. Outcomes of interest include the ACR20, ACR50, ACR70, total complication rate, and the occurrence of remission. Any disagreements between the reviewers were resolved by discussion and re-check of the article and consultation with a third reviewer. After reviewing and culling, 15 clinical trials comparing the clinical efficacy of TCZ and its comparators in the treatment of patients with RA entered the qualitative and quantitative synthesis. Tocilizumab 8 mg was statistically better than 4 mg or placebo for ACR responses. Significant clinical adverse events in patients with RA treated with TCZ, such as abnormal liver function tests (LFTs) and infections, were more frequent than in comparator groups. This systematic review and meta-analysis suggest that the combination therapy of TCZ with other drugs such as methotrexate and disease-modifying antirheumatic drugs has been studied for various clinical effects concerning safety and clinically significant adverse events. Although the data are promising, long-term performance and safety data need to be fully identified, as well as the risks and benefits of TCZ, especially appropriate timing, dosage, and regimen.
... 7 31 A detailed picture of clinical pathogenesis remains to be elucidated and may involve a complex interplay between viruses, HLA proteins, T cells, cytokine secretion and other genetic polymorphisms. 2 7 31 The conditions for which these inhibitors may be used are a large and expanding group. [32][33][34] We found scattered reports of DRESS or hypereosinophilia with rash implicating these drugs in RA, polyarthritis, undifferentiated autoinflammatory disorder, giant cell arteritis and COVID-related cytokine storm (online supplemental table S8). HLA typing was not included in these reports and will be important in future investigations. ...
... 27 A study of tocilizumab in RA had a 15% withdrawal rate for adverse events and/or failure to respond. 34 In 24 patients with COVID-19 treated with tocilizumab, posttreatment elevation of IL-6 levels identified the 25% who died. 35 Further work is needed to determine if hypersensitivity contributes to the rates of drug failures. ...
Objectives
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.
Methods
In a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.
Results
Still’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10 ⁻¹⁴ ). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10 ⁻¹³ ) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10 ⁻¹⁰ ). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.
Conclusions
DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.
... Tocilizumab Tocilizumab (TCZ, trade name: Actemra) is a recombinant humanized monoclonal antibody (Sheppard et al., 2017). TCZ is well-tolerated without significant abnormalities after long-term toxicity tests on animals (Gabay et al., 2013). For the mechanism of action, TCZ specially binds membrane-bound interleukin-6 receptor (mIL-6R) and soluble interleukin-6 receptor (sIL-6R) and inhibits signal transduction (Ibrahim et al., 2020). ...
Since the outbreak of corona virus disease 2019 (COVID-19) in Wuhan (China) in December 2019, the epidemic has rapidly spread to many countries around the world, posing a huge threat to global public health. In response to the pandemic, a number of clinical studies have been initiated to evaluate the effect of various treatments against COVID-19, combining medical strategies and clinical trial data from around the globe. Herein, we summarize the clinical evaluation about the drugs mentioned in this review for COVID-19 treatment. This review discusses the recent data regarding the efficacy of various treatments in COVID-19 patients, to control and prevent the outbreak.
... 6,7 The interleukin-6 inhibitors, tocilizumab and sarilumab, as well as the cluster of differentiation (CD)-80/CD86 inhibitor, abatacept, are also available in Japan for the treatment of RA. 6,7 In the few head-to-head randomized clinical trials that have assessed the comparative effectiveness of biologics in the treatment of RA, comparable efficacy has generally been demonstrated. [8][9][10][11][12][13][14] RA requires long-term treatment, and this can result in a high economic burden for patients, payers, and society. 15 In Japan, the annual drug cost of etanercept 50 mg/week is approximately U1.6 million. ...
... Evidence from 14 phase 3 clinical trials suggested that the immunogenicity risk of tocilizumab is low, regardless of the route of administration [206]. According to the ADACTA study, tocilizumab therapy was found to be more effective than adalimumab monotherapy in terms of reducing signs and symptoms in RA patients with an inadequate response to MTX therapy [207]. The most common side effects reported in clinical trials are upper respiratory tract infections, nasopharyngitis, cellulitis, and high blood pressure [202]. ...
Rheumatoid arthritis (RA) is a multifactorial autoimmune disease of unknown etiology, primarily affecting the joints, then extra-articular manifestations can occur. Due to its complexity, which is based on an incompletely elucidated pathophysiological mechanism, good RA management requires a multidisciplinary approach. The clinical status of RA patients has improved in recent years due to medical advances in diagnosis and treatment, that have made it possible to reduce disease activity and prevent systemic complications. The most promising results were obtained by developing disease-modifying anti-rheumatic drugs (DMARDs), the class to which conventional synthetic, biologic, and targeted synthetic drugs belong. Furthermore, ongoing drug development has led to obtaining molecules with improved efficacy and safety profiles, but further research is needed until RA turns into a curable pathology. In the present work, we offer a comprehensive perspective on the management of RA, by centralizing the existing data provided by significant literature, emphasizing the importance of an early and accurate diagnosis associated with optimal personalized treatment in order to achieve better outcomes for RA patients. In addition, this study suggests future research perspectives in the treatment of RA that could lead to higher efficacy and safety profiles and lower financial costs.
... targeted-synthetic DMARDs (tsDMARDs), with Janus kinase inhibitors (JAKi). [1][2][3][4][5][6][7][8][9] While all bDMARDs and tsDMARDs have demonstrated efficacy in randomised controlled trials, 1-9 these results are not always relevant to 'real-world patients', because of very restrictive inclusion criteria, numerous exclusion criteria and limited follow-up. 10 In addition, bearing in mind the number of current options available, head-to-head trials including several of the alternative treatment options would be impractical to realise. ...
Background: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.
Methods: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.
Results: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.
Conclusion: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.
... In addition to that, medications used to treat COVID-19 are responsible for indirect cardiovascular complications and adverse side effects [8][9][10][11]. COVID-19 drugs initiate different cardiovascular problems like bundle branch block, AV block, ventricular arrhythmia, cardiomyopathy, myocardial injury, hypertension, along so many other long-term complications [12][13][14][15][16][17]. Though conventional techniques like, Cardiac cell therapy and myocardial tissue engineering are capable of producing new tissues, studies show various limitations of these techniques that make these techniques impractical to use [18,19]. ...
Due to multiple mutations of SARS-CoV-2, the mystery of defeating the virus is still unknown. Cardiovascular complications are one of the most concerning effects of COVID-19 recently, originating from direct and indirect mechanisms. These complications are associated with long-term Cardio-vascular diseases and can induce sudden cardiac death in both infected and recovered COVID-19 patients. The purpose of this research is to do a competitive analysis between conventional techniques with the upgraded alternative 3D bioprinting to replace the damaged portion of the myocardium. Additionally, this study focuses on the potential of 3D bioprinting to be a novel alternative. Finally, current challenges and future perspective of 3D bioprinting technique is briefly discussed.
... IL-6, bir kompleks oluşturmak için sIL-6R'ye bağlanır, bu daha sonra sinyal transdüksiyonunu tamamlamak ve proinflamatuar bir rol oynamak için hücre zarı üzerindeki gp130'a bağlanır (8)(9)(10)(11). SSS tedavi yöntemlerinden bir diğeri olan Tosilizumab, IL-6 reseptörü monoklonal antikoru olarak sIL-6R ve mIL-6R'ye bağlanabilir ve sinyal transdüksiyonunu inhibe edebilir (11)(12)(13). Tosilizumabın şiddetli SSS 'li hastaların tedavisinde etkili olduğunu belirtmek gerekir (14,15). Çalışmamızın amacı, SARS-CoV-2 virüsünün tetiklediği SSS ve SF sonrası gelişen ARDS, sepsis, septik şok ve multiorgan yetmezliği tablolarındaki hastaların tedavi sürecinde uyguladığımız CPFA veya Tosilizumab tedavilerinin; hemodinami ve sağkalım oranları üzerindeki etkilerini dosya ve arşiv bilgilerinden tarayarak bilgi edinmek ve değerlendirmektir. ...
Abstract
Background: The novel coronavirus, which causes Covid-19 disease and is called severe acute respiratory syndrome coronavirus
2(SARS-CoV-2) by the World Health Organization, was first seen in Wuhan, China in December 2019 and initiated a pandemic on a
global scale. Uncontrolled cytokine production is observed in Covid-19 cases with severe progression, and this is thought to be one
of the reasons for increased mortality.
We applied Coupled Plasma Filtration Adsorption (CPFA) and Tocilizumab treatments to patients who were hospitalized in our
intensive care unit due to Covid-19 disease and who thought that cytokine release syndrome and/or cytokine storm developed after
the uncontrolled cytokine production triggered by the SARS-CoV-2 virus. In our study, we aimed to evaluate the effectiveness of
these treatments through retrospective file and archive scanning.
Materials and Methods: Patients who had hospitalized in our intensive care unit between February and June 2020 due to Covid-19
disease, were thought to have developed cytokine release syndrome and/or cytokine storm, and were treated with CPFA or
Tocilizumab were included in our study. Our study was planned by retrospectively scanning the data of 20 patients from each
treatment group.
CPFA treatments were applied for 10 hours each session and 2 sessions with a 12-hour break. Tocilizumab administration was made
intravenously within 1 hour from 8 mg/kg dose to a maximum of 800 mg.
Before CPFA and Tocilizumab treatments and in the 24th, 48th hour and 7th day after CPFA and Tocilizumab treatments, Sequential
Organ Failure Assessment scores(SOFA), Horowitz indexes(PaO2/FiO2), fever, inotrope requirements, SpO2 and relevant laboratory
values (IL-6, Lymphocyte count, CRP, D-dimer) were obtained from patient files and systemic data.
Results: After CPFA and Tocilizumab treatments, a decrease in fever and IL-6 values, an increase in SpO2 and lymphocyte values, an
increase in Horowitz and SOFA scores, and a decrease in CRP and D dimer values were observed. The increase in SpO2 and Horowitz
score values was significantly higher in the CPFA group. At the end of the 7th day, a decrease in fever values and an increase in SOFA
scores and a decrease in CRP - D dimer values were significantly more pronounced in the CPFA group. A decrease in inotropic support
was observed in the CPFA group.
Conclusion: In Covid-19 disease, the disease has a more severe course with cytokine release syndrome and/or cytokine storm that
develops after the deterioration of the immune system. Inflammatory cytokine production was controlled with CPFA and Tocilizumab
treatments, and improvements were achieved in the oxygenation and clinical findings of the patients.
Key words: Covid-19, Cytokine release syndrome, Cytokine storm, CPFA, Tocilizumab
Amaç: İlk olarak Aralık 2019’da Çin’in Wuhan kentinde ortaya çıkan ve Dünya Sağlık Örgütü(DSÖ) tarafından şiddetli akut
solunum yolu sendromu koronavirüsü (SARS-CoV-2) olarak adlandırılan yeni koronavirüs, Covid-19 hastalığına neden oldu ve küresel
ölçekte bir pandemi başlattı. Şiddetli progresyon gösteren Covid-19 olgularında kontrolsüz sitokin üretimi gözlenmekte ve bu
durumun artmış mortalitenin nedenlerinden biri olduğu düşünülmektedir.
Covid-19 hastalığı nedeniyle yoğun bakımımızda yatmakta olan ve SARS-CoV-2 virüsünün tetiklediği kontrolsüz sitokin üretimi sonrası
sitokin salınım sendromu ve/veya sitokin fırtınası geliştiğini düşündüğümüz hastalara Coupled Plasma Filtration Adsorption (CPFA)
ve Tosilizumab tedavileri uyguladık. Çalışmamızda bu tedavilerin etkinliklerini, geriye dönük dosya ve arşiv taraması üzerinden
değerlendirmeyi amaçladık.
Materyal ve Metod: Şubat-Haziran 2020 tarihleri arasında Covid-19 hastalığı sebebiyle yoğun bakım ünitemizde yatmış, sitokin
salınım sendromu ve/veya sitokin fırtınası geliştiği düşünülmüş ve tedavi amacıyla CPFA veya Tosilizumab uygulanmış hastalar
çalışmamıza dahil edildiler. Her iki tedavi grubundan 20’şer hastanın verileri retrospektif olarak tarandı.
CPFA uygulamaları, her seans 10 saat olacak şekilde ve 12 saat ara verilmek suretiyle 2 seans olarak yapılmıştır. Tosilizumab
uygulaması 8 mg/kg dozdan, maksimum 800 mg olacak şekilde, 1 saatlik sürede intravenöz yoldan yapılmıştır.
CPFA ve Tosilizumab uygulamaları başlamadan hemen önce, uygulamalar sonrası 24. saat, 48. saat ve 7. gün ölçülen Sequential
Organ Failure Assessment skoru(SOFA), Horowitz indeksi (PaO2/FiO2), ateş, inotrop varlığı, SpO2 ve ilgili laboratuvar değerleri (IL-6,
Lenfosit sayısı, CRP, D-dimer) hasta dosyalarından elde edildi ve karşılaştırmalar yapıldı.
Bulgular: CPFA ve Tosilizumab tedavileri sonrası her iki grupta da Horowitz ve SOFA skorları ile SpO2 ve lenfosit değerlerinde artış,
ateş, IL-6, CRP ve D dimer değerlerinde ise azalma meydana geldi. SOFA, Horowitz skoru ve SpO2 değerlerindeki artış, CPFA grubunda
anlamlı olarak daha yüksekti. Ek olarak, ateş, CRP ve D-dimer değerlerindeki düşme de yine CPFA grubunda anlamlı olarak daha
belirgindi. İnotrop desteğinde azalma CPFA grubunda daha belirgin olmasına rağmen istatistiksel açıdan anlamlı bir fark izlenmedi.
Sonuç: Covid-19 hastalığında bağışıklık sisteminin etkilenmesi sonrası gelişen sitokin salınım sendromu ve/veya sitokin fırtınası ile
hastalık daha ağır seyretmektedir. CPFA ve Tosilizumab tedavileri ile inflamatuar sitokin üretimi kontrol altına alınarak, hastaların
oksijenizasyonunda ve klinik bulgularında düzelmeler sağlanmıştır.
Anahtar Kelimeler: Covid-19, Sitokin salınım sendromu, Sitokin fırtınası, CPFA, Tosilizumab
... For example, whereas IL-6 receptor and IL-6 inhibition were successful in RA and vasculitis, this approach failed in psoriasis and axial SpA. IL-17A inhibition was efficacious in psoriasis, PsA and axial SpA, but not in RA nor IBD (see, for example, reFs [15][16][17]. Indeed, IL-17A inhibition may result in disease exacerbation in IBD, informing an important barrier function in the gut, which is independent of local IL-23p19 expression, as inhibition of IL-23p19 is more likely anti-inflammatory 18 . ...
Immune-mediated inflammatory diseases are common and clinically diverse. Although they are currently incurable, the therapeutic armamentarium for immune-mediated inflammatory diseases has been transformed in the past two decades. We have moved from the wide application of broad-spectrum immune modulators to the routine use of agents with exquisite specificity, arising from monoclonal and molecular biotechnology and more recently from highly targeted medicinal chemistry. Here we describe key advances and lessons that drove this remarkable progress and thereafter reflect on the next steps in this ongoing journey. In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.
... Tocilizumab (Actemra®) is a recombinant humanized monoclonal antibody that help in preventing binding of IL-6 with IL-6 receptors, and because of its anti-inflammatory action it has already been used for treating rheumatoid arthritis (RA) [106] . Tocilizumab is also known to be a biological disease modifying anti-rheumatic drug (BoDMARD) being used as an alternative to tumor necrosis factor (TNF-α) antagonist and methotrexate, having excellent safety profile [107] . ...
COVID-19 is a disease caused by the novel strain of
coronavirus also known as SARS-CoV-2 initially originated
in Wuhan, China. On March 11, 2019 it was officially
declared as a global pandemic by WHO. The viral
transmission was associated with respiratory droplets and
through other bodily secretions as well. The cellular entry of
virus was associated with angiotensin converting enzymes 2
receptors (ACE-2 receptors). This study was conducted from
December, 2020 to March, 2021. A total of 159 studies
related to immune pathogenesis and therapeutic profile of
COVID-19 were included. All studies involving
pharmacological therapies for treating COVID-19 were
included but the studies manifesting nutritional interventions
and herbal medications for treatment of COVID-19 were
excluded. Various data bases like Medline/PubMed, Scopus,
and web of science were used as a search engine. Fever,
cough, myalgia, headache and shortness of breath were
common symptoms associated with COVID-19. The clinical
spectrum of disease was ranging from asymptomatic carriers
to acute respiratory distress syndrome (ARDS) caused by
exaggerated inflammatory response also known as cytokine
storm (IL-6, IL-1, IL-8, IL-10), and hyperactivity of host
immune system (innate, cellular and humoral immune
system) leading to severe form of COVID-19. Various
therapeutic options used to treat COVID-19 are
corticosteroids, antimalarials (hydroxychloroquine and
chloroquine), antivirals (Remdesivir, lopinavir/ritonavir),
antibiotics (azithromycin), interleukin-6 inhibitors
(tocilizumab), Plasma exchange, and finally the most
effective and economical treatment is through vaccine which
is now considered definitive treatment option. However,
more studies are required to explore the most effective, safer
and accessible treatment options to treat and prevent COVID-
19.
... Tocilizumab is also FDA-approved for the treatment of giant cell arteritis, polyarticular juvenile idiopathic arthritis, and cytokine release syndrome. [42][43][44][45][46] The risks of inhibiting IL-6 or IL-6R are similar and include injection-site reactions, more frequent infections, liver dysfunction, neutropenia and thrombocytopenia, hypercholesterolemia and hypertriglyceridemia, bowel perforation, and (very rarely) demyelination. To mitigate the risk of liver dysfunction and cell count dyscrasia, a safety lab monitoring protocol was developed for dose reductions when baseline or monitoring safety lab thresholds were met (see Table E3 in this article's Online Repository at www.jacionline.org). ...
Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma.
... 6,7 The interleukin-6 inhibitors, tocilizumab and sarilumab, as well as the cluster of differentiation (CD)-80/CD86 inhibitor, abatacept, are also available in Japan for the treatment of RA. 6,7 In the few head-to-head randomized clinical trials that have assessed the comparative effectiveness of biologics in the treatment of RA, comparable efficacy has generally been demonstrated. [8][9][10][11][12][13][14] RA requires long-term treatment, and this can result in a high economic burden for patients, payers, and society. 15 In Japan, the annual drug cost of etanercept 50 mg/week is approximately U1.6 million. ...
Objectives
To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX.
Methods
Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span.
Results
Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772.
Conclusion
These results suggest that maintenance treatment with etanercept 25 mg is cost-effective.
... Following rituximab's success, anti-CD20 depleting antibodies such as ofatumumab, ocrelizumab and veltuzumab were developed and are currently in phase II and phase III clinical trials [24][25] . Results of these trials are not yet published or released. ...
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation of synovium, cartilage damage and co-occurring of various other disorders. Significant improvement has been achieved in RA therapeutics in last two decades. However, newer, more efficient and more cost-effective therapeutic applications are still needed to be developed. Current therapies in RA are mostly acting to restrict inflammation. Non steroidal anti inflammatory drugs (NSAIDs) and disease modifying antirheumatic drugs (DMARDs) are conventionally used in RA therapy. Studies showed higher efficacy of anticytokine therapy such as anti-IL-6 and anti-TNF. Rituximab, targeting B cells, after establishing its potential was approved to be used in combination with methotrexate in 2006. Abatacept, CLTA-4-IgG1, has been developed to block CD28 and CD80 or CD86 interaction leading to the termination T cell activation. Molecular inhibitors are relatively new in RA therapeutics such as tocilizumab, tofacitinib and baricitinib. FDA has approved tofacitinib to be used as a treatment for moderate and severe RA. Future holds promising therapeutic options based on numerous studies. IL-12, IL-17 and IL-23 are the targets of future anticytokine therapies. Several lymphocyte targeting agents including ofatumumab, ocrelizumab and veltuzumab have been developed and are currently in phase II and phase III clinical trials. There is a vast range of potential targets in RA enabling us to expand the therapeutic options over the next decade.
... Selecting a broad range of patients with different underlying pathologies, be it immune mediated or not, may hamper the final results when studying the effects of, for instance, tocilizumab. Tocilizumab has already been investigated as a monotherapy in RA with favorable results (77). It therefore seems less logical to exclude patients from a trial in which a common pathogenic cytokine is targeted. ...
Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.
... More clear and easy approaches are needed. For example, in rheumatoid arthritis with the exception of a few clinical situations (Poddubnyy, 2021) (e.g., superiority of tocilizumab compared with adalimumab-a TNF inhibitor-in patients requiring monotherapy (Gabay et al., 2013); somewhat better response to abatacept compared with adalimumab in patients with poor prognostic factors, including a high concentration of anticitrullinated protein antibodies (Fleischmann et al., 2019); and an overall better response to rituximab in patients who are seropositive compared with patients who have seronegative rheumatoid arthritis (Courvoisier et al., 2021)), there are currently no markers that could be used for a precision medicine approach in clinical practice. ...
... Blockade of IL-6 biologic activity with the help of IL-6R neutralizing antibodies has been approved in many countries. The blockade of IL-6 activity is highly successful and has been shown to be equivalent or superior to the blockade of the cytokine TNFα (Gabay et al., 2013;Burmester et al., 2017). Interestingly, we have shown that specific blockade of IL-6 trans-signaling was as effective as the blockade of global IL-6 activity by a neutralizing antibody indicating that IL-6 trans-signaling represents the pro-inflammatory IL-6 activity whereas IL-6 signaling via the membrane bound IL-6R was rather protective e.g., in the case of bacterial infections (Sodenkamp et al., 2012;Hoge et al., 2013). ...
Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.
... MARD with demonstrated consistent evidence of efficacy in monotherapy for symptomatic control and inhibition of radiographic progression 83,130,[132][133][134][135] . However, in a recent analysis of the tocilizumab randomized trials, combination therapy with tocilizumab plus MTX proved to be more effective in preventing radiographic progression when compared to tocilizumab-monotherapy 136 . ...
Objective:
To update the recommendations for the treatment of rheumatoid arthritis (RA) with biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs), endorsed by the Portuguese Society of Rheumatology (SPR).
Methods:
These treatment recommendations were formulated by Portuguese rheumatologists taking into account previous recommendations, new literature evidence and consensus opinion. At a national meeting, in a virtual format, three of the ten previous recommendations were re-addressed and discussed after a more focused literature review. A first draft of the updated recommendations was elaborated by a team of SPR rheumatologists from the SPR rheumatoid arthritis study group, GEAR. The resulting document circulated among all SPR rheumatologists for discussion and input. The level of agreement with each of all the recommendations was anonymously voted online by all SPR rheumatologists.
Results:
These recommendations cover general aspects such as shared decision, treatment objectives, systematic assessment of disease activity and burden and its registry in Reuma.pt. Consensus was also achieved regarding specific aspects such as initiation of bDMARDs and tsDMARDs, assessment of treatment response, switching and definition of persistent remission.
Conclusion:
These recommendations may be used for guidance of treatment with bDMARDs and tsDMARDs in patients with RA. As more evidence becomes available and more therapies are licensed, these recommendations will be updated.
... Despite its crucial role in B cell maturation, anti-IL-6 therapy failed to show therapeutic efficacy in patients with multiple myeloma (55). However, IL-6-targeted therapy with tocilizumab, the first anti-IL-6Rblocking mAb, was shown to have significant clinical benefits in RA and was even superior to adalimumab in efficacy (56). Tocilizumab is currently approved for the treatment of RA, JIA, AOSD, giant cell arteritis, and cytokine releasing syndrome based on its ability to regulate systemic hyperinflammation (54). ...
In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.
... The tremendous success of IL-6 targeting agents for RA treatment may be due to several factors. First, the efficacy of TCZ supersedes that of adalimumab in RA patients (45). Second, TCZ monotherapy shows comparable clinical efficacy to the combined therapy of TCZ and MTX, whereas anti-TNF-α monotherapy demonstrates lower clinical efficacy than anti-TNF-α combined with MTX. ...
Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.
... Among studies whose reference treatment was combination therapy of adalimumab originator and methotrexate (MTX), four compared adalimumab to its biosimilars [25][26][27][28], two studies compared adalimumab to tofacitinib [29,30] and one each for adalimumab compared to abatacept [31], certolizumab pegol [32], baricitinib [33], upadacitinib [34] and filgotinib [35]. Among studies whose reference treatment was adalimumab originator monotherapy, three studies compared adalimumab originator to its biosimilar [36][37][38], and one each for tocilizumab [39] and sarilumab [40], respectively. Figure 2 shows the mixed treatment comparison design, in which the reference treatment is adalimumab originator with or without MTX compared to all other targeted therapies (see Figure legend). ...
Few studies compared adalimumab to other targeted therapies in head-to-head randomized clinical trials (RCTs) for rheumatoid arthritis (RA), but multiple comparisons are not available. This Bayesian Network Meta-Analysis evaluated which targeted therapy is more likely to achieve ACR50 response with good safety at 24 weeks of treatment in RA. A systematic literature review was conducted for head-to-head phase 3 RCTs that compared adalimumab to other targeted therapies in combination with methotrexate (MTX) or as monotherapy to treat RA patients, and searched through MEDLINE, EMBASE, Cochrane Library and Clinicaltrial.gov. The outcomes of interest were ACR50 response and withdrawals due to adverse events at 24 weeks. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a random effect model. Sixteen studies were included in the analysis. The most favorable SUCRA for the ACR50 response rate at 24 weeks of treatment in combination with MTX was ranked by upadacitinib, followed by baricitinib, tofacitinib and filgotinib. As monotherapy, the highest probability was ranked by tocilizumab followed by sarilumab. No significant differences in safety profile among treatment options were found. Jak-inhibitors in combination with MTX and interleukin-6 antagonism as monotherapy showed the highest probability to achieve ACR50 response after 24 weeks of treatment. None of assessed targeted therapies were associated to risk of withdrawal due to adverse events. Key messages: Direct and indirect comparison between adalimumab and other targeted therapies demonstrated some differences in terms of efficacy that may help to drive RA treatment. Jak-inhibitors and interleukine-6 antagonists ranked as first in the probability to achieve ACR50 response after 24 weeks of treatment in combination with methotrexate or monotherapy, respectively.
... The JAK pathway participates in both hematopoiesis 31 and lipid metabolism. [32][33][34] While they have been approved as therapeutics for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, oral JAK inhibitors have led to alterations in the levels of lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. 35 A recent study with the oral JAK inhibitor tofacitinib has reported an increased risk of all-cause mortality, including sudden cardiovascular (CV) death relative to patients on tumor necrosis factor inhibitors, in older patients with CV risk factors. ...
Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase 1, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n=66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc) radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 hours across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding–corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways.99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase 1 at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.
... The decrease in ferroptosis and lipid ROS levels induced by TNF could be eliminated by adalimumab, a fully human monoclonal TNF antibody (Fig. 5e, f) that has been approved for the treatment of RA, juvenile idiopathic arthritis, ankylosing spondylitis, and inflammatory bowel disease 27 . Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody 28 , inhibited IL-6-enhanced cell death and lipid peroxidation in fibroblasts treated with IKE or RSL3 (Fig. 5g). The increased ferroptotic response caused by TGF-β was also effectively rescued by SB431542, a selective inhibitor of activin receptor-like kinase (ALK) receptors that are type I receptors in the TGF-β superfamily (Fig. 5h). ...
Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.
... Die Anti-IL-6-Rezeptor-Antikörper Tocilizumab und Sarilumab sind beide zur Behandlung der RA zugelassen und effektiv. Klinische Studien haben für die Monotherapie ohne den Kombinationspartner MTX eine gute Wirksamkeit gezeigt [14,15], sodass eine Kombination mit MTX bei den IL-6-Inhibitoren nicht notwendig ist [5]. Für Tocilizumab existiert in der Rheumatologie außerdem eine Zulassung zur Behandlung der Riesenzellarteriitis, nicht jedoch für die SpA inklusive der PsA. ...
Biologics are an integral part of modern strategies for treatment of rheumatoid arthritis (RA) and spondylarthritis (SpA), including psoriatic arthritis (PsA). Biologics are biotechnologically produced proteins that have inhibiting effects on humoral and cellular components of rheumatic inflammation. Substance classes used in rheumatology are tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL‑6, IL-12, IL-17 and IL-23 inhibitors effective against cytokines as well as the T lymphocyte activation inhibitor abatacept and the B lymphocyte-depleting rituximab. There are clear recommendations for the use of biologics for RA patients inadequately responding to one or more conventional synthetic disease-modifying antirheumatic drugs and for ankylosing spondylitis (AS) and nonradiographical axial SpA patients with an inadequate response to at least two nonsteroidal antirheumatic drugs. For PsA the recommended use depends on the most prominent manifestations in each case. Treatment with biologics should follow the treat to target principle, with a defined and validated treatment target. Treatment in cases of RA and SpA should target remission or at least a low or minimum disease activity. The safety of treatment with biologics has been intensively investigated. There are very specific contraindications for individual substance classes with a focus on an increased risk of infections. The standard procedure before starting treatment with biologics includes the exclusion of latent tuberculosis and hepatitis B. The TNF-alpha inhibitors have a protective effect with respect to myocardial infarction, stroke and venous thromboembolism.
... 21 The IL-6 inhibitors have been demonstrated to have greater efficacy than TNF inhibitors when used as monotherapy without concurrent csDMARD, as demonstrated in head-to-head trials with adalimumab. 22,23 This represents a role for these agents in patients in whom csDMARDs are either poorly tolerated or contraindicated. Similar to TNF inhibitors, switching from one IL-6 inhibitor to another after failure of the first is possible but in general an alternative class is preferred. ...
Kate E Findeisen,1,* Julia Sewell,1,* Andrew JK Ostor2,3 1The Alfred Hospital, Melbourne, Victoria, Australia; 2Cabrini Medical Centre, Melbourne, Victoria, Australia; 3Monash University, Melbourne, Victoria, Australia*These authors contributed equally to this workCorrespondence: Andrew JK OstorCabrini Medical Centre, Melbourne, Victoria, AustraliaTel +61 3 9509 4244Email andrewostor@gmail.comAbstract: Rheumatoid arthritis (RA) is a disease characterised by inflammation of synovial joints and poses a substantial healthcare burden on both the individual and society. One of the most significant shifts in the RA therapeutic landscape has occurred with the introduction of biological disease modifying anti-rheumatic drugs (bDMARDs). There are five classes of bDMARDs currently available, each with a different molecular target and subtle differences in their efficacy and safety profile. This review also describes the “real-world” use of bDMARDs and how they fit into the overall RA treatment guidelines.Keywords: rheumatoid arthritis, biological therapies, bDMARDs
Bergenin is a natural PPARγ agonist that can prevent neutrophil aggregation, and often be used in clinics for treating respiratory diseases. Recent data show that Th17 cells are important for neutrophil aggregation and asthma through secreting IL-17A. In this study, we investigated the effects of bergenin on Th17 differentiation in vitro and subsequent neutrophilic asthma in mice. Naïve T cells isolated from mouse mesenteric lymph nodes were treated with IL-23, TGF-β, and IL-6 to induce Th17 differentiation. We showed that in naïve T cells under Th17-polarizing condition, the addition of bergenin (3, 10, 30 μM) concentration-dependently decreased the percentage of CD4+ IL-17A+ T cells and mRNA expression of specific transcription factor RORγt, and function-related factors IL-17A/F, IL-21, and IL-22, but did not affect the cell vitality and apoptosis. Furthermore, bergenin treatment prevented GLS1-dependent glutaminolysis in the progress of Th17 differentiation, slightly affected the levels of SLC1A5, SLC38A1, GLUD1, GOT1, and GPT2. Glutamine deprivation, the addition of glutamate (1 mM), α-ketoglutarate (1 mM), or GLS1 plasmid all significantly attenuated the above-mentioned actions of bergenin. Besides, we demonstrated that bergenin (3, 10, and 30 μM) concentration-dependently activated PPARγ in naïve T cells, whereas PPARγ antagonist GW9662 and siPPARγ abolished bergenin-caused inhibition on glutaminolysis and Th17 differentiation. Furthermore, we revealed that bergenin inhibited glutaminolysis by regulating the level of CDK1, phosphorylation and degradation of Cdh1, and APC/C-Cdh1-mediated ubiquitin-proteasomal degradation of GLS1 after activating PPARγ. We demonstrated a correlation existing among bergenin-affected GLS1-dependent glutaminolysis, PPARγ, “CDK1-APC/C-Cdh1” signaling, and Th17 differentiation. Finally, the therapeutic effect and mechanisms for bergenin-inhibited Th17 responses and neutrophilic asthma were confirmed in a mouse model of neutrophilic asthma by administration of GW9662 or GLS1 overexpression plasmid in vivo. In conclusion, bergenin repressed Th17 differentiation and then alleviated neutrophilic asthma in mice by inhibiting GLS1-dependent glutaminolysis via regulating the “CDK1-APC/C-Cdh1” signaling after activating PPARγ.
Aim
The increased level of interleukin-6 (IL-6) plays a significant role in the pathogenesis of rheumatoid arthritis (RA). Specific blockade of IL-6 or its receptor has been used successfully in treating RA. MicroRNAs can regulate gene expression and act as regulators of target genes. Manipulation of specific microRNAs provides a novel therapeutic strategy for treating/preventing diseases. This study explored the role of miR-98-5p in the regulation of IL-6 expression in rheumatoid fibroblast-like synoviocytes (RA-FLSs).
Methods
Real-time PCR was used to detect miR-98-5p expression in RA-FLSs and normal human fibroblast-like synovial cells (HFLSs). Site-directed gene mutagenesis and reporter gene assay were performed to identify the interaction between miR-98-5p and IL-6. Manipulation of miR-98-5p expression in RA-FLS used transfection with miR-98-5p mimic or inhibitor. Stimulation of FLSs with IL-1β induced IL-6 production. Enzyme-linked immunosorbent assay was used to detect the level of IL-6 secreted into the RA-FLS culture supernatant.
Results
Compared with HFLSs, the expression of miR-98-5p in RA-FLSs was significantly downregulated, and was negatively correlated with DAS28 scores and rheumatoid factor. In patients with anti-keratin antibody-positive RA, the expression level of miR-98-5p was lower. miR-98-5p negatively regulated the expression of IL-6 in RA-FLSs. After IL-1β stimulation, the expression of miR-98-5p decreased and the level of IL-6 protein was upregulated during IL-6 secretion.
Conclusion
These data suggest that manipulation of miR-98-5p, which negatively modulates IL-6 expression, may be a potential clinical approach in RA.
Eduardo Mysler, Mariana Caubet, Ana Lizarraga Organización Medica de Investigación, Buenos Aires, ArgentinaCorrespondence: Eduardo Mysler Email e.mysler@omiargentina.com.arAbstract: Rheumatoid arthritis (RA) is the most prevalent form of inflammatory arthritis. It is a profoundly serious and severe disease that if it goes untreated could have severe consequences to the joints and health of the patient who carries this diagnosis. The treatment of RA has dramatically changed since the year 2000, with the discovery of the TNFis, then other biologics, and finally the JAKi. All these new medications with or without methotrexate in combination, tight control and treat to target have produced a revolution in the outcome of this disease. We reviewed and summarized the treatment options, and the most significant papers for each one of these new drugs. The reader could have a full picture with all the references of the recent publications. We also updated the biosimilar situation in RA, as well as the new drugs that will be coming to the market in the next 5 years.Keywords: rheumatoid arthritis, DMARDs, biosimilars
Inflammation is a basal host defense response that eliminates the causes and consequences of infection and tissue injury. Macrophages are the primary immune cells involved in the inflammatory response. When activated by LPS, macrophages release various pro-inflammatory cytokines, chemokines, inflammatory mediators, and MMPs. However, unbridled inflammation causes further damage to tissues. Safinamide is a selective and reversible monoamine oxidase B (MAOB) inhibitor that has been used for the treatment of Parkinson's disease. In this study, we aimed to investigate whether safinamide has effects on LPS-treated macrophages. Our results show that safinamide inhibited the expression of pro-inflammatory cytokines such as IL-1α, TNF-α, and IL-6. Furthermore, safinamide suppressed the production of CXCL1 and CCL2, thereby preventing leukocyte migration. In addition, safinamide reduced iNOS-derived NO, COX-2-derived PGE2, MMP-2, and MMP-9. Importantly, the functions of safinamide mentioned above were found to be dependent on its inhibitory effect on the TLR4/NF-κB signaling pathway. Our data indicates that safinamide may exert a protective effect against inflammatory response.
IntroductionThe 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).MethodsA 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.ResultsIn 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.
Cytokines are immune effector molecules that regulate the immune response but also contribute to autoimmunity and are a prime target for therapeutic intervention. This chapter reviews the immunobiology of key cytokines in systemic lupus erythematosus, their regulatory and effector functions, and current progress in therapeutic intervention.
Introduction:
Rheumatoid arthritis (RA) pathogenesis is driven by a complex network of proinflammatory cytokines, among which interleukin-6 (IL-6) plays a key role in inducing and perpetuating chronic inflammation. Targeting the IL-6 pathway has shown to be an invaluable treatment strategy, as demonstrated by the results accrued in the last decade with the first IL-6 inhibitor, tocilizumab. More recently, a second monoclonal antibody blocking IL-6, sarilumab, has enriched our armamentarium by proving outstanding efficacy in RA treatment.
Areas covered:
After exploring the IL-6 pathway under physiological conditions and in the RA pathogenesis, in this review we discuss the pharmacologic properties of sarilumab and the clinical trials that constitute the sarilumab development program and have enabled its licensed application.
Expert opinion:
Results from clinical trials confirmed the efficacy and safety of sarilumab for the treatment of RA, similar to its precursor tocilizumab. Blocking IL-6 pathway results in comprehensive control of the disease, from both physician's and patient's perspective, and of RA comorbidities and extra-articular manifestations which are largely IL-6 driven. Finally, the proven efficacy of sarilumab as monotherapy arises the drug as a required therapeutic alternative considering the large proportion of patients intolerant or inadequate to receive conventional synthetic disease-modifying drugs (csDMARDs).
Biological disease-modifying anti-arthritis drugs (bDMARD) have transformed rheumatoid arthritis (RA) treatment and allowed many patients to reach clinical remission. With the huge growth in the development of different bDMARDs, there is now a need to decide on which treatment should be prescribed to achieve optimal patient outcomes. Decisions are made by weighing up the comparative efficacy of each agent against risks, namely the risk of bacterial infections. The most powerful tools for investigating the comparative efficacy of bDMARDs are head-to-head trials that directly compare one therapy to another; however, very few trials of this type exist. Furthermore, the heterogeneity of RA calls for consideration of the comparative efficacy of therapies on an individual basis. Many studies have found associations between specific biomarkers and response to different bDMARDs to enable stratification of patient groups, although many results have not been reproducible in different cohorts. Combining predictors to create models of treatment response may be the ultimate key to finding reliable biomarkers with enough predictive power to enable a personalised medicine approach to treating RA in the clinic.
Interleukin-6 (IL-6) is considered an inflammatory cytokine, which is involved not only in most inflammatory states but it also plays a prominent role in inflammation associated cancers. The response of cells to the cytokine strictly depends on the presence of the IL-6 receptor (IL-6R),which presents IL-6 to the signal transducing receptor subunit gp130, which is expressed on all cells of the body. The expression of IL-6R is limited to some cells, which are therefore IL-6 target cells. The IL-6R can be cleaved by proteases and the thus generated soluble IL-6R (sIL-6R) still binds the ligand IL-6. The complex of IL-6 and sIL-6R can bind to gp130 on any cell, induce dimerization of gp130 and intracellular signaling. This process has been named IL-6 trans-signaling. A fusion protein of soluble gp130 with the constant portion of human IgG1 (sgp130Fc) turned out to be a potent and specific inhibitor of IL-6 trans-signaling. In many animal models of human diseases the significance of IL-6 trans-signaling has been analyzed. It turned out that the activities of IL-6 mediated by the sIL-6R are the pro-inflammatory activities of the cytokine whereas activities of IL-6 mediated by the membrane-bound IL-6R are rather protective and regenerative. The sgp130Fc protein has recently been developed into a biologic. The possible consequences of a specific IL-6 trans-signaling blockade is discussed in the light of the recent successfully concluded phase II clinical trials in patients with inflammatory bowel disease.
Background and Objective
Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are used either when conventional synthetic DMARDs are ineffective or when disease activity is high and with poor prognostic factors, based on various clinical guidelines. The purpose of this study was to investigate the prescribing trends of bDMARDs for patients with rheumatoid arthritis in Japan, and to clarify whether the pharmacological therapy of bDMARDs is administered based on guidelines.Methods
We conducted a descriptive epidemiological study from 2012 to 2018 using the JMDC Claims Database, a nationwide claims database, and described the annual changes based on the number of patients prescribed bDMARDs. Anti-rheumatic drugs were identified based on the Anatomical Therapeutic Chemical codes, including methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs and bDMARDs.ResultsFrom the database including 6,862,244 people, the data of 6407 patients with rheumatoid arthritis were extracted. The present study demonstrated that the proportion of patients prescribed bDMARDs was 1.0 per 1000 people, with those aged ≥ 65 years being the most common age group. The proportion of patients with rheumatoid arthritis who were prescribed bDMARDs increased significantly over time (p < 0.0001). Additionally, the concomitant proportions of methotrexate (p < 0.0001), non-steroidal anti-inflammatory drugs (p < 0.0001) and glucocorticoids (p = 0.0001) prescribed with bDMARDs decreased significantly over time.Conclusions
The increase in bDMARD monotherapy may be attributed to the new bDMARDs that have been launched sequentially; furthermore, physicians have come to recognise monotherapy as the mainstay of treatment. Future studies must accumulate evidence on the long-term efficacy and safety of bDMARDs.
Rheumatoid arthritis (RA) is an autoimmune disease, mainly characterized by erosional arthritis. The proportion of adults suffering from RA is about 0.5%–1%. There have been reports on the association of rainfall and traffic-related air pollutants with RA hospitalization rates. However, there have been no studies on the association of diurnal temperature range (DTR) and relative humidity (RH) with RA hospitalization rates. This study aimed to examine the short-term association of DTR, RH and other meteorological factors with the hospital admission rate of RA patients, while excluding the interference of PM2.5, SO2, NO2, CO and O3 atmospheric pollutants. We collected daily RA occupancy rate and meteorological factor data in Hefei city from 2015 to 2018 and used the generalized additive model (GAM) combined with the distributed lag nonlinear model (DLNM) for time series analysis, and further stratified analysis by gender and age. Single-day and cumulative-day risk estimates of RA admissions were expressed as relative risk (RR) and its 95% confidence interval (95% CI). For the cumulative-day lag model, high RH was statistically significant after cumulative lag 0–8 days, and the effect gradually increases. Stratified analysis shows that females seem to be more susceptible to high or extremely high DTR and RH exposure, and extremely high DTR exposure may increase the risk of RA admission in all populations. In conclusion, this study found that high DTR and high RH exposure increased the risk of hospitalization in RA patients and provided clues to the potential association between other meteorological factors and RA.
This chapter explores the role of interleukin (IL)-6 in autoimmune disorders. It starts by providing a historical perspective and exploring the mechanisms responsible for IL-6 signaling. It then describes the pleiotropic effects of IL-6 and several autoimmune and autoimmune-related disorders where IL-6 expression is deregulated, along with laboratory clues of IL-6 overexpression. In the second part of this chapter, the role of IL-6 blockade in autoimmune disorders is explored. For tocilizumab and sarilumab, important studies that have led to their approval in rheumatoid arthritis, juvenile idiopathic arthritis, and giant cell arteritis are briefly presented. For these two anti-IL-6 drugs, data is also presented regarding safety, contraindications, pharmacodynamics, pharmacokinetics, drug interactions, warnings, and immunogenicity. Finally, IL-6 blockade off-label use is discussed, pointing to the most valuable evidence not only in the abovementioned disorders but also in other autoimmune diseases whose management may be achieved by specifically blocking IL-6 signaling.
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
Objective
The aim of this study was to update the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA) (JCR CPG for RA) according to recent changes in the medical environment in Japan. This article is a digest version of the guidance.
Methods
We used the Grading of Recommendations, Assessment, Development, and Evaluation method to update the 2014 JCR CPG for RA. A consensus was formed by CPG panel members.
Results
We identified 36 important clinical questions regarding drug treatment and developed corresponding recommendations for RA. The recommendations included the following RA medications: non-steroidal anti-inflammatory drugs, corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, biological disease-modifying antirheumatic drugs, anti-RANKL antibodies, and JAK inhibitors, as well as the tapering and discontinuation of these medications. Recommendations regarding the efficacy and safety of treatments in the elderly and patients with comorbidities were also developed. Finally, we used these recommendations to create an original algorithm for drug treatment for RA based on the Treat-to-Target approach.
Conclusion
The 2020 JCR CPG for RA provides a useful tool for rheumatologists, health care professionals, and patients with RA, enabling shared decision making in a variety of clinical situations.
As citocinas são proteínas que transduzem sinais em células após ligação em receptores específicos, induzindo uma cascata de sinalização intracelular e transcrição gênica. A interleucina-6 (IL-6) é uma das citocinas mais importantes do corpo com papel na regulação de diferentes processos fisiológicos e patológicos, como em doenças inflamatórias crônicas, autoimunes, infecciosas e neoplásicas. Na cascata de sinalização da IL-6, a citocina ativa seu receptor através de três vias diferentes, clássica, transinalização ou transapresentação, posteriormente desencadeando sinalização intracelular pela via da JAK/STAT; assim, a IL-6 está intimamente relacionada com a imunidade inata e adaptativa. No sistema imune, a IL-6 é a principal indutora dos reagentes de fase aguda e modula respostas de linfócitos T e B. Desse modo, o bloqueio da via da IL-6 com imunobiológicos é um alvo terapêutico para doenças inflamatórias, como doenças reumáticas imunomediadas (DRIM), neoplasias e infecções. O bloqueio da via da IL-6, especialmente com tocilizumabe, já é uma realidade para diversas DRIM, por exemplo, artrite reumatoide, artrite idiopática juvenil e arterite de células gigantes. Outras DRIM, neoplasias e infecções, como COVID-19, têm a aplicação do bloqueio da via da IL-6 como uma novidade terapêutica. Este artigo revisa os diferentes aspectos fisiológicos da sinalização da via da IL-6, a participação da IL-6 em processos patológicos, os modos de bloqueio terapêutico da via da IL-6, as doenças tratadas e seus estudos clínicos disponíveis. Unitermos: Interleucina-6. Tocilizumabe. Doenças reumáticas imunomediadas. Artrite reumatoide.
Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4 , reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.
Background
JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.
Methods
In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.
Results
We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.
Conclusion
The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.
Introduction:
the aim of our study is to determine, from data of the Moroccan register of biotherapies, the factors influencing the choice of the first prescribed biological treatment.
Methods:
cross-sectional multicenter study including rheumatoid arthritis patients who were initiated the first biological treatment either: Rituximab, an anti-TNF, or Tocilizumab. The determinants related to the patient and disease have been gathered. A univariate and then multivariate analysis to determine the factors associated with the choice of the first bDMARDs was realized.
Results:
a total of 225 rheumatoid arthritis patients were included in the Moroccan registry. The mean age was 52 ± 11 years, with female predominance 88% (n = 197). The first prescribed biological treatment was Rituximab 74% (n = 166), the second one was Tocilizumab, 13.6% (n = 31) then comes the anti-TNF in 3rd position with 12.4% (n = 28). The factors associated with the choice of Rituximab as the first line bDMARDs prescribed in univariate analysis were: the insurance type, the positivity of the rheumatoid factor. In multivariate analysis, only the insurance type that remains associated with the choice of Rituximab as the first biological drugs. The Tocilizumab was associated with shorter disease duration and was more prescribed as mono-therapy compared to non Tocilizumab group. TNFi was associated with the insurance type.
Conclusion:
our study suggests that Rituximab and TNFi are associated with the type of insurance and Tocilizumab is the most prescribed biologic mono-therapy in RA patients. Further studies are needed to confirm these results.
A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
Objective
In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.
Methods
Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28–erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.
Results
Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28–ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant–Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.
Conclusion
No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.
To identify a specific pattern of serum cytokines that correlates with the diagnosis, activity and severity of rheumatoid arthritis (RA) in patients with early RA as well as with the level of serum markers of B cell activation.
Serum interleukin (IL)-1β, IL-1 receptor antagonist (IL1-Ra), IL-2, IL-4, IL-6, IL-10, IL-17, IL-21, monocyte chemotactic protein 1 (MCP-1), tumour necrosis factor α and interferon γ levels were measured in the (ESPOIR) Etude et Suivi des POlyarthrites Indifférenciées Récentes early arthritis cohort, which included patients with at least two swollen joints for >6 weeks and <6 months, and no previous corticosteroids or disease-modifying antirheumatic drugs. Serum cytokine levels were compared between patients who met the 1987 American College of Rheumatology criteria for RA (n=578) or had undifferentiated arthritis (UA, n=132) at the 1-year follow-up visit.
Serum IL-6 and IL-21 were the only cytokines that discriminated RA from UA on univariate analysis. IL-6 level was associated with RA, whereas erythrocyte sedimentation rate and C-reactive protein were not. Higher proportions of rheumatoid factor and anticyclic citrullinated protein (CCP) positivity, levels of markers of B cell activation, and a higher frequency of rapid radiographic progression were observed in patients with RA with detectable IL-6 or IL-21. Multivariate analysis associated IL-6 and anti-CCP levels with radiographic erosions at enrolment with 1-year radiographic progression.
Serum IL-6 concentration is greater in RA than in UA. Increase in serum IL-6 and IL-21 levels is associated with markers of B cell activation, and IL-6 is associated with radiographic progression in patients with RA.
To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA).
This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan-Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference.
One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence.
These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.
Clinical registries have shown their effectiveness in capturing the long-term benefit of drugs in routine care. In France, two types of registry have been established to analyse the safety and efficacy of biological agents.
The Research Axed on Tolerance of Biotherapies (RATIO) registry was designed to prospectively collect all cases of lymphoma and opportunistic infections occurring in patients receiving anti-TNF blockers for any indication. We also examined the results from nationwide prospective cohorts in order to investigate the safety and efficacy of rituximab (RTX), abatacept (ABA) and tocilizumab in RA and other autoimmune diseases.
Analysis of the RATIO registry demonstrated an increased risk of Legionella pneumophila infection in patients receiving anti-TNF therapy, a higher risk of tuberculosis [odds ratio (OR) (95% CI): 13.3 (2.6, 69.0) and 17.1 (3.6, 80.6) for infliximab and adalimumab vs etanercept, respectively], opportunistic infections and incidence of lymphoma, with mAb than with soluble-receptor anti-TNF. The characteristics of RA patients in RTX and ABA registries showed that some patients did not receive previous TNF blockers [20% in autoimmunity and RTX (AIR) and 13% in Orencia and RA (ORA)] and one-third of them were treated without concomitant DMARDs. Patients receiving RTX showed an increased proportion of severe infections (5.0/100 patient-years). Lung and cardiac comorbidities, extra-articular involvement and low immunoglobulin G before RTX were predictive factors of severe infections. In addition, the AIR registry suggested the effectiveness of RTX in patients with SLE.
The establishment of biological registries in rheumatic diseases, in France, with their different methods, has already provided additional data to controlled trials, mainly on the risk of severe infections and lymphoma.
RA is a chronic, debilitating disease in which articular inflammation and joint destruction are accompanied by systemic manifestations including anaemia, fatigue and osteoporosis. IL-6 is expressed abundantly in the SF of RA patients and is thought to mediate many of the local and systemic effects of this disease. Unlike a number of other cytokines, IL-6 can activate cells through both membrane-bound (IL-6R) and soluble receptors (sIL-6R), thus widening the number of cell types responsive to this cytokine. Indeed, trans-signalling, where IL-6 binds to the sIL-6R, homodimerizes with glycoprotein 130 subunits and induces signal transduction, has been found to play a key role in acute and chronic inflammation. Elevated levels of IL-6 and sIL-6R in the SF of RA patients can increase the risk of joint destruction and, at the joint level, IL-6/sIL-6R can stimulate pannus development through increased VEGF expression and increase bone resorption as a result of osteoclastogenesis. Systemic effects of IL-6, albeit through conventional or trans-signalling, include regulation of acute-phase protein synthesis, as well as hepcidin production and stimulation of the hypothalamo-pituitary-adrenal axis, the latter two actions potentially leading to anaemia and fatigue, respectively. This review aims to provide an insight into the biological effects of IL-6 in RA, examining how IL-6 can induce the articular and systemic effects of this disease.
Objective of the study is to investigate how compliance during the first year of methotrexate (MTX) treatment in rheumatoid arthritis (RA) is influenced by the patients' perception of the necessity for and concern about MTX, the patients' functional disability, and the dose of MTX. A total of 126 RA patients completed a questionnaire at start of MTX treatment and after 9 months. The MTX compliance was measured by using the Compliance Questionnaire Rheumatology (CQR). The prevalence of having a CQR score in the bottom quartile was stratified according to age, gender, the duration of RA, MTX dose, years of school education, functional disability, use of folic acid, and co-morbidity. Crude and adjusted prevalence ratios (PR) with 95% confidence intervals (CI) were calculated by using log-binomial regression. The necessity and concern scales of the Beliefs about Medication Questionnaire were dichotomised into high perception of MTX necessity and low concern about MTX treatment, and the crude and adjusted PR of having a CQR score in the bottom quartile were estimated. The prevalence of having a CQR in the bottom quartile was 23%, both at baseline and after 9 months, and this finding was not associated with the MTX dose level or the patients' functional disability. Among patients with a CQR in the bottom quartile, the prevalence of having low perceptions of MTX necessity was 37.1 versus 14.0% for patients with high perceptions of necessity [adjusted PR: 0.3 (95% CI 0.2-0.8)]. The same tendency was seen after 9 months. The prevalence of having a CQR in the bottom quartile or not was almost equally distributed among patients who had high or low concerns about treatment at baseline. After 9 months, however, the prevalence of having a CQR in the bottom quartile was 18.9% for patients who had low concerns about the MTX treatment, versus 37.7% for patients who had higher concerns about the treatment [adjusted PR: 0.5 (95% CI 0.2-1.3)]. During the first year of treatment, compliance with MTX treatment among RA patients could be explained by strong perceptions of a personal need for the treatment. Compliance did not seem to be influenced by the patients' functional impairment or the MTX dose level.
The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.
To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.
This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.
The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively.
Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.
To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA).
A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied.
88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a-2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b-4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4).
This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.
We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
The course of rheumatoid arthritis (RA) is highly variable, ranging from a mild self-limiting to a very aggressive form. To follow and predict the course of the disease in an individual patient, several recognized and proposed prognostic markers, including markers for disease activity, have been considered. However, no individual marker for disease activity has shown satisfactory specificity and sensitivity. Thus an index of disease activity combining several variables is needed. Response criteria based on the Disease Activity Score (DAS) were developed in an open study of 227 patients with RA of recent onset. Response was defined as a combination of a significant change from baseline and the level of disease activity attained. Good response was defined as a significant decrease in DAS (> 1.2) and a low level of disease activity ( < or = 2.4). Non-response was defined as a decrease < or = 0.6, or a decrease > 0.6 and < or = 1.2 with an attained DAS > 3.7. Any other scores were regarded as moderate responses. These response criteria were adopted as the EULAR response criteria and were validated, together with the WHO/ILAR and ACR response criteria, in a 48 week, double-blind trial comparing hydroxychloroquine and sulphasalazine in 60 patients. Response was evaluated against radiographic damage (construct validity) and functional disability (criterion validity); discriminating capacity was also assessed. EULAR response criteria showed significant association with X-ray progression and functional disability, and differentiated between sulphasalazine and hydroxychloroquine. ACR and WHO/ILAR response criteria performed less well, only showing good criterion validity. Several groups are working on the prognosis of early RA and have agreed to collaborate to test DAS and other prognostic markers to better recognize severe, progressive RA, before joint damage takes place.
To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed.
In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI).
After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05).
Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.
We investigated the frequency of remission according to the disease activity score (DAS28) definition, modified American Rheumatology Association (ARA) criteria, and the frequency of an achievement of a functional status above defined thresholds ('functional remission', 'physical independence') in rheumatoid arthritis (RA) patients treated with either biologics or conventional DMARDs. We used the data of a prospective cohort study, the German biologics register RABBIT (German acronym for Rheumatoid Arthritis--Observation of Biologic Therapy) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics (BIOL; n = 818) or a conventional DMARD (n = 265). Logistic regression analysis was applied to adjust for differences in baseline risks. Taking risk indicators such as previous DMARD failures or baseline clinical status into account, we found that biologics doubled the chance of remission compared to conventional DMARD therapies (DAS28 remission, adjusted odds ratio (OR) 1.95 (95% confidenece interval (CI) 1.2-3.2)); ARA remission, OR 2.05 (95% CI 1.2-3.5)). High remission rates (DAS28 remission, 30.6%; ARA remission, 16.9%) were observed in BIOL patients with a moderate disease activity (DAS28, 3.2 to 5.1) at the start of treatment. These rates decreased to 8.5% in patients with DAS28 > 6. Sustained remission at 6 and 12 months was achieved in <10% of the patients. Severely disabled patients (< or = 50% of full function) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence (> or = 67% of full function) than controls (OR 3.88 (95% CI 1.7-8.8)). 'Functional remission' (> or = 83% of full function) was more often achieved in BIOL than in controls (OR 2.18 (95% CI 1.04-4.6)). In conclusion, our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence. However, temporary or even sustained remission remain ambitious aims, which are achieved in a minority of patients only.
The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers.
First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account.
Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years.
Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.
Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune responses and inflammatory reactions. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) and, therefore, an agent blocking IL-6 actions can be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit glycoprotein (gp) 130. This family also includes IL-11, oncostatin-M, and leukemia inhibitory factor (LIF). In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of gp130. Tocilizumab is a humanized antihuman IL-6 receptor antibody designed using genetic engineering technology. Tocilizumab recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 actions. Tocilizumab is expected to ameliorate the autoimmune inflammatory diseases with IL-6 overproduction and has been clinically developed as a therapeutic agent for RA, systemic-onset and articular types of JIA, Crohn's disease, etc. Tocilizumab has been shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of RA. Immunopharmacology and clinical benefit of tocilizumab in RA is addressed.
The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.
499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.
ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.
Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.
NCT00106522.
Methotrexate (MTX) has become the first-line treatment for rheumatoid (RA) and psoriatic arthritis (PsA); however, few studies have focused on its tolerability. The objective of our analyses was to study RA and PsA patients in whom MTX was discontinued, the reasons for this and the duration of MTX treatment prior to withdrawal. A retrospective electronic database review was undertaken to identify all patients who had received MTX for RA or PsA. Patients who had discontinued MTX were then identified, and the reasons for this were categorised. The duration of MTX treatment was assessed in those who had stopped treatment due to intolerability. A total of 1,257 patients who had received MTX were identified [762 (61 %) RA and 193 (15 %) PsA]. MTX had been stopped in 260 (34 %) patients with RA and 71 (36 %) patients with PsA most commonly due to gastrointestinal intolerability. The median duration of MTX treatment was 10 months in both groups, mean duration 21 and 18.6 months in RA and PsA groups, respectively. Overall, one third of patients with RA and PsA stop MTX most commonly due to poor tolerability. In the context of chronic disease, the median duration of treatment is short (10 months). Our analysis did not include patients who suffer from side effects but continue therapy; thus, the magnitude of the problem may be substantially greater therefore as poor tolerability impacts treatment adherence.
Objective. The development and validation of Modified Disease Activity Scores (DAS) that include different 28-joint counts.
Methods. These scores were developed by canonical discriminant analyses and validated for criterion, correlational, and construct validity. The influence of disease duration on the composition of the DAS was also investigated.
Results. No influence of disease duration was found. The Modified DAS that included 28-joint counts were able to discriminate between high and low disease activity (as indicated by clinical decisions of rheumatologists).
Conclusion. The Modified DAS are as valid as disease activity scores that include more comprehensive joint counts.
LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.
In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.
Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).
Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.
The Veterans Affairs (VA) Rheumatoid Arthritis (VARA) registry and the VA Pharmacy Benefits Management database were linked to determine the association of methotrexate (MTX) adherence with rheumatoid arthritis (RA) disease activity.
For each patient, the medication possession ratio (MPR) was calculated for the first episode of MTX exposure of a duration of ≥12 weeks for both new and established MTX users. High MTX adherence was defined as an MPR ≥0.80 and low MTX adherence was defined as an MPR <0.80. For each patient, the mean Disease Activity Score with 28 joints (DAS28) score, erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) level observed during registry followup were compared in high- versus low-adherence groups.
In 455 RA patients, the prescribed doses of MTX (mean ± SD 16 ± 4 mg versus 16 ± 4 mg; P = 0.6) were similar in high-adherence patients (n = 370) in comparison to low-adherence patients (n = 85). However, the actual observed MTX doses taken by patients were significantly higher in the high-adherence group (mean ± SD 16 ± 5 mg versus 11 ± 3 mg; P < 0.001). DAS28 (mean ± SD 3.6 ± 1.2 versus 3.9 ± 1.5; P < 0.02), ESR (mean ± SD 24 ± 18 versus 29 ± 24 mm/hour; P = 0.05), and CRP level (mean ± SD 1.2 ± 1.3 versus 1.6 ± 1.5 mg/dl; P < 0.03) were lower in the high-adherence group compared to those with low MTX adherence. These variances were not explained by differences in baseline demographic features, concurrent treatments, or whether MTX was initiated before or after VARA enrollment.
High MTX adherence was associated with improved clinical outcomes in RA patients treated with MTX. Adjustment for potential confounders did not alter the estimated effect of adherence. These results demonstrate the advantages of being able to merge clinical observations with pharmacy databases to evaluate antirheumatic drugs in clinical practice.
To assess the efficacy and safety of tocilizumab plus methotrexate (MTX) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX.
A total of 1,196 patients were enrolled in a 2-year, randomized, double-blind, placebo-controlled trial. Patients received tocilizumab (8 mg/kg or 4 mg/kg) or placebo every 4 weeks plus MTX. Rescue treatment was available from week 16. Results from year 1 are presented.
Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P < 0.0001 for both comparisons). Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Questionnaire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg (-144.1 and -128.4 units, respectively) than with placebo (-58.1 units; P < 0.0001 for both comparisons). Proportions of patients with American College of Rheumatology 20%, 50%, and 70% improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo (P < 0.0001 for all comparisons). The safety profile of tocilizumab was consistent with the profiles in previous studies. Infections were the most common adverse and serious adverse events.
The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone. Tocilizumab has a well-characterized safety profile.
Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition.
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes.
Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3.
We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.
To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations.
We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995-2005. Initiators of DMARDs and oral glucocorticoids were followed for < or =180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference.
We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor alpha antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1-1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%.
Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.
Studies have suggested that early institution of tumor necrosis factor (TNF) inhibitors improves functional status and slows radiographic progression among patients with rheumatoid arthritis (RA). To determine whether these findings have altered practice patterns, we used the Consortium of Rheumatology Researchers of North America (CORRONA) registry to assess the pattern of TNF inhibitor utilization in the US over time.
Demographics and disease activity data were collected for patients with RA. The trend of TNF inhibitor use during 2002-06 was evaluated prospectively using linear and logistic regression models.
Of the 11,397 patients with RA, 66% and 34% had established RA and early RA (disease duration < 3 yrs), respectively. The majority of patients were female and Caucasian. Despite comparable levels of disease activity, more of the patients with established RA were taking TNF inhibitors than those with early RA (40% vs 25%; p < 0.0001). The majority of patients (70%) taking TNF inhibitors were also receiving disease modifying antirheumatic drugs. The use of TNF inhibitors increased at a rate of 2.8% per year in established RA and 1.2% per year in early RA. The mean Clinical Disease Activity Index at the start of TNF inhibitors decreased at a rate of -0.233 per quarter (p = 0.006), while the mean Disease Activity Score decreased at a rate of -0.04 per quarter (p = 0.022).
Utilization of TNF inhibitors in this multicenter, observational US cohort is increasing in both early and established RA, although it is more prominent among patients with established RA. The level of disease activity at which TNF inhibitors were initiated decreased over time in patients with both established and early RA.
To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).
A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.
At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.
Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.
A structure for representation of patient outcome is presented, together with a method for outcome measurement and validation of the technique in rheumatoid arthritis. The paradigm represents outcome by five separate dimensions: death, discomfort, disability, drug (therapeutic) toxicity, and dollar cost. Each dimension represents an outcome directly related to patient welfare. Quantitation of these outcome dimensions may be performed at interview or by patient questionnaire. With standardized, validated questions, similar scores are achieved by both methods. The questionnaire technique is preferred since it is inexpensive and does not require interobserver validation. These techniques appear extremely useful for evaluation of long term outcome of patients with rheumatic diseases.