In vitro neutralization of IL-6 receptor exacerbates damage to intestinal epithelial cells during Mycobacterium avium paratuberculosis infection.

Like TNFα, IL-6 is upregulated in Crohn's disease (CD) especially in patients associated with Mycobacterium avium paratuberculosis (MAP) infection, and both cytokines have been targeted as a therapeutic option for the treatment of the disease despite the accepted partial response in some patients. Limited response to anti-IL-6 receptor-neutralizing antibodies therapy may be related to the homeostatic dual role of IL-6. In this study, we investigated the effects and the signaling mechanism of IL-6 involved in intestinal epithelial integrity and function during MAP infection using an in vitro model that consists of THP-1, HT-29 and Caco-2 cell lines. Clinically, we determined that plasma samples from MAP-infected CD patients have higher IL-6 levels compared to controls (P-value < 0.001). In CD-like macrophages, MAP infection has significantly upregulated the secretion of IL-6 and the shedding of (IL-6R) from THP-1 macrophages, P-value < 0.05. Intestinal cell lines (Caco-2 and HT-29) were treated with the supernatant of MAP-infected THP-1 macrophages with or without a neutralizing anti-IL-6R antibody. Treating intestinal Caco-2 cells with supernatant of MAP-infected macrophages resulted in significant upregulation of intestinal damage markers including claudin-2 and SERPINE1/PAI-1. Interestingly, blocking IL-6 signaling exacerbated that damage and further increased the levels of the damage markers. In HT-29 cells, MAP infection upregulated MUC2 expression, a protective response that was reversed when IL-6R was neutralized. More importantly, blocking IL-6 signaling during MAP infection rescued damaged Caco-2 cells from MAP-induced apoptosis. The data clearly supports a protective role of IL-6 in intestinal epithelia integrity and function especially in CD patients associated with MAP infection. The findings may explain the ineffective response to anti-IL6 based therapy and strongly support a therapeutic option that restores the physiologic level of IL-6 in patient's plasma. A new treatment strategy based on attenuation of IL-6 expression and secretion in inflammatory diseases should be considered.

Selective inhibition of interleukin 6 receptor decreased inflammatory cytokines and increased proteases in an experimental model of critical calvarial defect.

Considering the lack of consensus related to the impact of selective IL-6 receptor inhibition on bone remodeling and the scarcity of reports, especially on large bone defects, this study proposed to evaluate the biological impact of the selective inhibitor of interleukin-6 receptor (tocilizumab) in an experimental model of critical calvarial defect in rats. In this preclinical and in vivo study, 24 male Wistar rats were randomly divided into two groups (n=12/group): defect treated with collagen sponge (CG) and defect treated with collagen sponge associated with 2 mg/kg tocilizumab (TCZ). The defect in the parietal bone was created using an 8-mm diameter trephine drill. After 90 days, the animals were euthanized, and tissue samples (skull caps) were evaluated through micro-CT, histological, immunohistochemistry, cytokines, and RT-qPCR analyses. Tocilizumab reduced mononuclear inflammatory infiltration (P<0.05) and tumor necrosis factor (TNF)-α levels (P<0.01) and down-regulated tissue gene expression of BMP-2 (P<0.001), RUNX-2 (P<0.05), and interleukin (IL)-6 (P<0.05). Moreover, it promoted a stronger immunostaining of cathepsin and RANKL (P<0.05). Micro-CT and histological analyses revealed no impact on general bone formation (P>0.05). The bone cells (osteoblasts, osteoclasts, and osteocytes) in the defect area were similar in both groups (P>0.05). Tocilizumab reduced inflammatory cytokines, decreased osteogenic protein, and increased proteases in a critical bone defect in rats. Ninety days after the local application of tocilizumab in the cranial defect, we did not find a significant formation of bone tissue compared with a collagen sponge.

The Cytokine Storm of Multicentric Castleman Disease.

As described throughout this book, different triggers can elicit a variety of different cytokine storm disorders that share overlapping clinical features (Fig. 31.1). Even within a particular cytokine storm disorder, multiple different triggers can elicit the syndrome. Like HLH, multicentric Castleman disease (MCD) serves as a great example of this as it can be caused by a viral infection, neoplastic cell population, or an unknown cause. Furthermore, the idiopathic subtype of MCD (iMCD) provides one of the first examples of a cytokine storm disorder that could be abrogated with targeted neutralization of a single cytokine when inhibition with the anti-interleukin-6 (IL-6) receptor monoclonal antibody tocilizumab was shown to effectively treat iMCD in the 1990s. Of course, this "iMCD treatment," tocilizumab, has been used in a variety of cytokine storm settings over the last 30+ years.

IL-6 Blockade in Cytokine Storm Syndromes.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine elevated in cytokine storm syndromes, including hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). It is also elevated in cytokine release syndrome (CRS) after immune activating cancer therapies such as chimeric antigen receptor (CAR) T-cells or bispecific T-cell engagers (BITEs) and in some patients after infection with SARS-CoV-2. The interaction of IL-6 with its receptor complex can happen in several forms, making effectively blocking this cytokine's effects clinically challenging. Fortunately, effective clinical agents targeting the IL-6 receptor (tocilizumab) and IL-6 directly (siltuximab) have been developed and are approved for use in humans. IL-6 blockade has now been used to safely and effectively treat several cytokine storm syndromes (CSS). Other methods of investigation in effective IL-6 blockade are underway.

De novo design of miniprotein antagonists of cytokine storm inducers.

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1ß. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects.

[Preliminary study on the role and mechanism of IL-6 receptor antagonists in improving post-infarction ventricular arrhythmia].

Objective: To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. Methods: The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Results: Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP (P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower (P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group (P all<0.05). Conclusions: TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Interleukin-6 Signaling Blockade Induces Regulatory Plasmablasts in Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Interleukin-6 receptor antibodies (IL-6R Abs), including satralizumab, are increasingly used to prevent relapse for neuromyelitis optica spectrum disorder (NMOSD). However, the detailed mechanism of action of this treatment on the lymphocyte phenotype remains unclear. This study focused on B cells in patients with NMOSD, hypothesizing that IL-6R Ab enables B cells to acquire regulatory functions by producing the anti-inflammatory cytokine IL-10. METHODS: Peripheral blood mononuclear cells were stimulated in vitro to induce the expansion of B-cell subsets, double-negative B cells (DNs; CD19+ IgD-, CD27-) and plasmablasts (PBs; CD19+, CD27hi, CD38hi). Whole B cells, DNs, or PBs were isolated after culture with IL-6R Ab, and IL-10 expression was quantified using quantitative PCR and a cytometric bead array. RNA sequencing was performed to identify the marker of regulatory PBs induced by IL-6R Ab. RESULTS: DNs and PBs were observed to expand in patients with NMSOD during the acute attacks. In the in vitro model, IL-6R Ab increased IL-10 expression in B cells. Notably, IL-10 expression increased in PBs but not in DNs. Using RNA sequencing, CD200 was identified as a marker of regulatory PBs among the differentially expressed upregulated genes. CD200+ PBs produced more IL-10 than CD200- PBs. Furthermore, patients with NMOSD who received satralizumab had a higher proportion of CD200+ PBs than patients during the acute attacks. DISCUSSION: Treatment with IL-6 signaling blockade elicited a regulatory phenotype in B cells and PBs. CD200+ PBs may be a marker of treatment responsiveness in the context of NMOSD pathophysiology.

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors.

The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.

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

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

Effect of IL-6R blockade on plasma lipids and clinical outcomes among hospitalized patients with COVID-19 infection.

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.

The fibroid phenotype of biological naïve patients with rheumatoid arthritis are less likely to respond to anti-IL-6R treatment.

Type III collagen gene expression is upregulated in the synovium of patients with rheumatoid arthritis (RA) presenting the fibroid phenotype. The soluble type III collagen formation biomarker, PRO-C3, is known to measure fibrogenesis in fibrotic diseases. In this exploratory study, we aimed to investigate the association between fibrogenesis (PRO-C3) and the disease- and treatment response in patients with RA. We measured PRO-C3 in subsets of two clinical trials assessing the effect of the anti-interleukin-6 (IL-6) receptor treatment tocilizumab (TCZ) as monotherapy or polytherapy with methotrexate. PRO-C3 levels had weak or very weak correlations with the clinical parameters (Spearman's). However, when the patients were divided into Disease Activity Score-28 groups characterized by the erythrocyte sedimentation rate (DAS28-ESR), there was a statistical difference between the PRO-C3 levels of the different groups (p < 0.05). To determine the response in relation to PRO-C3, a cut-off based on PRO-C3 levels and patients in remission (DAS28-ESR ≤ 2.6) was identified. This showed that a reduction in PRO-C3 after treatment initiation was associated with decreased DAS28-ESR and a higher response rate in patients with low PRO-C3 levels than in those with high PRO-C3 levels. This indicates that a fibrotic component affects the responsiveness of patients.

Evaluation of interleukin-1 and interleukin-6 receptor antagonists in a murine model of acute lung injury.

The acute exudative phase of acute respiratory distress syndrome (ARDS), a severe form of respiratory failure, is characterized by alveolar damage, pulmonary oedema, and an exacerbated inflammatory response. There is no effective treatment for this condition, but based on the major contribution of inflammation, anti-inflammatory strategies have been evaluated in animal models and clinical trials, with conflicting results. In COVID-19 ARDS patients, interleukin (IL)-1 and IL-6 receptor antagonists (IL-1Ra and IL-6Ra, kineret and tocilizumab, respectively) have shown some efficacy. Moreover, we have previously developed novel peptides modulating IL-1R and IL-6R activity (rytvela and HSJ633, respectively) while preserving immune vigilance and cytoprotective pathways. We aimed to assess the efficacy of these novel IL-1Ra and IL-6Ra, compared to commercially available drugs (kineret, tocilizumab) during the exudative phase (day 7) of bleomycin-induced acute lung injury (ALI) in mice. Our results first showed that none of the IL-1Ra and IL-6Ra compounds attenuated bleomycin-induced weight loss and venous P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ increase. Histological analyses and lung water content measurements also showed that these drugs did not improve lung injury scores or pulmonary oedema, after the bleomycin challenge. Finally, IL-1Ra and IL-6Ra failed to alleviate the inflammatory status of the mice, as indicated by cytokine levels and alveolar neutrophil infiltration. Altogether, these results indicate a lack of beneficial effects of IL-1R and IL-6R antagonists on key parameters of ALI in the bleomycin mouse model.

Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.

BACKGROUND: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING: The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.

Tocilizumab (anti-IL-6) treatment for AA renal amyloidosis in a patient with advanced chronic kidney disease, a case report.

Systemic amyloid A amyloidosis is a progressive condition in which sustained elevation of serum amyloid A protein concentration leads to widespread amyloid deposition resulting in multiorgan failure without treatment. The kidney is the most commonly affected organ, and renal amyloid A amyloidosis can cause nephrotic syndrome and chronic kidney disease (CKD) leading to end stage kidney disease (ESKD). Serum Amyloid A protein is produced in the liver in response to chronic inflammation, specifically by inflammatory cytokines, especially IL-6. Tocilizumab, a monoclonal antibody that targets the interleukin-6 receptor, has increasingly been of interest in treating amyloid A amyloidosis. We present a case of a 79-year-old male with long-term seronegative polyarthritis who was referred with gradual decline in kidney function and nephrotic range proteinuria. His renal biopsy showed amyloid A amyloidosis with significant interstitial fibrosis and tubular atrophy. He was commenced on monthly tocilizumab infusions and peritoneal dialysis with good clinical response and rapid resolution of his nephrotic state. This case adds to the current literature on the benefits of tocilizumab in treating amyloid A amyloidosis in patients with advanced CKD.

Streptococcal toxic shock syndrome due to Streptococcus dysgalactiae subsp. equisimilis from retroperitoneal panniculitis during the treatment with anti-IL-6 receptor antibody: A case report.

A 53-year-old man with adult-onset Still's disease developed severe streptococcal toxic shock syndrome (STSS) due to Streptococcus dysgalactiae subsp. equisimilis (SDSE), following retroperitoneal panniculitis. He was receiving tocilizumab (TCZ), an interleukin-6 receptor inhibitor. The modifying effect of TCZ on the immune response and the pathophysiology of SDSE infection may have led to retroperitoneal panniculitis and atypical STSS with delayed shock and flare of soft tissue inflammation.

Serum Concentrations of Interleukin 6 in the General Adult Population: Possible Implications for Anti-IL-6 Therapy in SARS-Cov-2 Infection and IL-6-Related Diseases

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Eficacia y seguridad de tocilizumab para manejo de artritis reumatoide o artritis reumatoide juvenil con falla a tratamiento convencional de primera línea / Efficacy and safety of tocilizumab for the management of rheumatoid arthritis or juvenile rheumatoid arthritis with failure a conventional first-line treatment

INTRODUCCIÓN: Este documento técnico se realiza a solicitud del Seguro Integral de Salud (SIS) ­ Gerencia de Riesgo y Evaluación de Prestaciones (GREP). A. Cuadro clínico La Artritis Reumatoide (AR) es una enfermedad sistémica crónica autoinmune que se caracteriza por inflamación de articulaciones sinoviales y erosión cartilaginosa. Esta enfermedad produce limitación física, discapacidad y muerte prematura. Las complicaciones contribuyen al deterioro de las actividades sociales, la salud emocional y la calidad de vida. Por otra parte, la artritis idiopática juvenil (AIJ) se define como la presencia de artritis en una o varias articulaciones desde antes de los 16 años y que persiste por lo menos seis semanas, sin otra etiología conocida. La AIJ es la enfermedad reumática inflamatoria crónica más frecuente en la infancia. Los fármacos usados para las AR y AIJ incluyen a los analgésicos tipo AINES, corticoides, además también de los fármacos modificadores de la enfermedad (FARMEs). Existe la indicación de iniciar terapia biológica en pacientes no respondedores a la primera línea de tratamento. B. Tecnología sanitaria El Tocilizumab (TCZ) es un anticuerpo monoclonal humanizado, del grupo de los agentes biológicos con función inhibitoria del receptor de interleucina-6 (IL-6). La IL-6 promueve la activación de las células T y la diferenciación de las células B en células plasmáticas secretoras de inmunoglobulinas. Esta Interleucina proinflamatoria es producida por múltiples células, y tiene capacidad de estimular la diferenciación del osteoclasto que podría ser responsable de la destrucción articular. Esto tiene especial implicancia debido a que la actividad de la AR se correlaciona con niveles elevados de IL-6 en el líquido sinovial y en el suero. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura de TCZ para AR o AIJ con fracaso terapéutico a la primera línea de tratamiento. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de reumatología, y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se identificaron dos RS, dos ECA, cuatro GPC, seis ETS y una EE peruana. CONCLUSIONES La evidencia con respecto a TCZ en AR y ARJ es abundante. Las RS y ECAs identificados demuestran que TCZ es efectivo en AR y ARJ comparado con placebo, pero se asocia a más eventos adversos entre los más importantes se encuentran el aumento de LDH y otros factores de riesgo cardiovascular. Comparado con otros medicamentos biológicos, a través de comparaciones indirectas, no se evidencia superioridad. Las ETS y GPC seleccionadas coinciden en recomendar a TCZ como segunda línea de tratamiento y no mencionan a la tecnología por sobre otra. Una evaluación económica con perspectiva peruana de EsSalud concluye la dominancia de abatacept frente a otros medicamentos biológicos incluido TCZ en pacientes con AR moderada a severa con falla a MTX.

Seguridad del sarilumab en pacientes con artritis reumatoide / Safety of sarilumab in patients with rheumatoid arthritis

La artritis reumatoide es una enfermedad inflamatoria, crónica y sistémica, que afecta a las articulaciones periféricas generalmente de forma simétrica. El conocimiento cada vez mayor de las vías patogénicas ha permitido el desarrollo de nuevos fármacos y ampliar las opciones terapéuticas. La interleucina (IL) 6 parece jugar un papel fundamental en la patogenia de la artritis reumatoide. Por ello, el receptor de esta interleucina parece una diana interesante. Inicialmente, el tocilizumab demostró eficacia y seguridad en el tratamiento de la artritis reumatoide. El sarilumab es otro anticuerpo monoclonal dirigido frente al receptor de la IL-6 que, a la vista de los resultados obtenidos en los diferentes ensayos clínicos, muestra una eficacia y perfil de seguridad óptimos en el tratamiento de la artritis reumatoide, totalmente acorde con el bloqueo de la señalización de IL-6, cuya dosis recomendada es de 200 mg cada 2 semanas y, en caso de anormalidades de laboratorio, estas pueden gestionarse reduciendo la dosis a 150 mg cada 2 semanas

Rheumatoid arthritis is a chronic, inflammatory and systemic disease that affects the peripheral joints, usually symmetrically. The increased knowledge of pathogenic pathways has allowed the development of new drugs, thus expanding the therapeutic options. Interleukin-6 seems to play a key role in the pathogenesis of rheumatoid arthritis. Therefore, the interleukin-6 receptor seems to be an interesting target. Initially, tocilizu mab demonstrated efficacy and safety in the treatment of rheumatoid arthritis. Sarilumab is another monoclonal antibody directed against the interleukin-6 receptor which, based on the results obtained in the various clinical trials, shows an optimal efficacy and safety profile in the treatment of rheumatoid arthritis. The safety profile of sarilumab is consistent with the known effect of IL-6 inhibition. The recommended dose is 200 mg every two weeks and, if there are laboratory abnormalities, the dose can be reduced to 150 mg every two weeks

Tocilizumab para el tratamiento de la artritis reumatoidea / Tocilizumab for the treatment of rheumatoid arthritis

INTRODUCCIÓN: La artritis reumatoidea (AR) es una enfermedad crónica, más frecuente en mujeres, caracterizada por inflamación poliarticular y simétrica, con posible compromiso sistémico. La prevalencia en Argentina es de 2 por 1000 habitantes. Es causa de discapacidad laboral y aumento significativo de la mortalidad. Para su tratamiento, se utilizan diferentes fármacos tradicionales denominados drogas modificadoras de la AR (DMAR), siendo el metotrexate el de primera elección. En los casos de respuesta inadecuada o intolerancia a estos medicamentos, se recomienda el tratamiento con agentes biológicos, incluyendo a los inhibidores del TNF alfa (anti TNF), u otros agentes biológicos como el tocilizumab. TECNOLOGÍA: El tocilizumab es un anticuerpo monoclonal humanizado, inhibidor del receptor de la interleuquina 6 (IL- 6). Fue aprobado por FDA, EMA y ANMAT para el tratamiento de la AR de moderada a severa con respuesta inadecuada o intolerancia a una o más DMAR convencionales o a anti TNF. Se administra en forma endovenosa en dosis de 8 mg/kg/mes. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de tocilizumab en pacientes con AR. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas DARE, NHS EED, MEDLINE, en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS) y económicas (EE), guías de práctica clínica (GPC) y políticas de cobertura de otros sistemas de salud. RESULTADOS: Se incluyeron en el reporte un meta-análisis directo y dos indirectos, un ECA, tres GPC, dos ETS y doce políticas de cobertura. Se describen los resultados principales. Tocilizumab comparado con DMARs: Un meta-análisis directo publicado en el 2013 (incluyó quince ECAs que comparaban tocilizumab con algún DMAR, incluyendo un total de más de 5.500 pacientes) demostró la eficacia de tocilizumab en pacientes vírgenes de DMAR, con falla previa a DMAR o a anti TNF, encontrándose una respuesta ACR (índice compuesto que evalúa la mejoría de la actividad de la enfermedad con respecto al nivel basal) 20, 50 y 70 a la semana 24, significativamente superior en los pacientes tratados con tocilizumab que en los grupos controles, así como una diferencia significativa en la reducción de la progresión radiológica a favor del mismo. Tres de los estudios evaluaban la monoterapia (tocilizumab vs. DMAR) y en el resto, se comparó tocilizumab con una DMAR (usualmente metotrexate) versus DMAR sólo. Tocilizumab comparado con otros agentes biológicos: El único ECA publicado comparó monoterapia con tocilizumab versus adalimumab (325 pacientes) en sujetos en los que fuese inapropiado continuar tratamiento con metotrexate. Mostró una reducción significativamente superior del DAS 28 (índice compuesto para evaluar la respuesta clínica) en la rama de tocilizumab. Un meta-análisis indirecto, del 2012 (más de 16.000 pacientes), analizó la eficacia de diferentes agentes biológicos combinados con DMAR en pacientes con falla a DMAR convencionales, no encontrando diferencias significativas en las respuestas ACR 20, 50 y 70 entre etanercept y tocilizumab. Otro meta análisis indirecto publicado en el mismo año (1.873 pacientes) encontró respuestas similares en ACR 20, 50 y 70 entre tocilizumab y otros agentes biológicos, en sujetos con falla a anti TNF. Las GPC europeas y las argentinas de 2013, consideran adecuado el uso de terapias biológicas, entre las que se encuentra el tocilizumab como alternativa, en pacientes con falla o intolerancia a un tratamiento previo con DMARs o anti TNF. Las guías europeas también lo recomiendan como opción ante falla a agentes biológicos diferentes a anti TNF. Las GPC estadounidenses (2012) recomiendan la indicación de agentes anti TNF en los pacientes con respuesta inadecuada a DMARs; en los casos de falla a esta segunda línea de tratamiento se recomienda cambiar de terapia biológica, siendo una de las opciones el tocilizumab.Una ETS del Reino Unido, de 2012, que utiliza una evaluación económica, considera la indicación de tocilizumab como una alternativa más a otros agentes biológicos ante falla a DMARs, así como ante respuesta inadecuada a anti TNF y contraindicación a rituxumab. Una ETS estadounidense del mismo año afirma que no hay evidencia suficiente que avale la superioridad de un agente biológico sobre otro. Respecto de las políticas de cobertura, ocho financiadores de Estados Unidos cubren tocilizumab sólo en casos de falla al tratamiento con agentes anti TNF, mientras que cuatro también lo contemplan en caso de falla a DMARs. CONCLUSIONES: Existe evidencia de alta calidad metodológica acerca de la eficacia del tratamiento con tocilizumab en pacientes con AR moderada a severa; sin embargo, no existe evidencia adecuada acerca de la eficacia comparativa con otros agentes biológicos. Un único estudio comparativo mostró que en pacientes que no pueden recibir metotrexate, tocilizumab es clínica y estadísticamente más eficaz como monoterapia comparado con adalimumab monoterapia; sin embargo, no existen otros ECAs que hayan evaluado su efectividad respecto a otros agentes biológicos y estudios basados en comparaciones indirectas sugieren que es similar a etanercept. Algunas guías internacionales contemplan su uso como una alternativa más en caso de respuesta inadecuada a DMARs, otras guías sólo ante falla a anti TNF u otros agentes biológicos. Ante esta situación la decisión de cobertura dependerá del costo relativo del tocilizumab respecto al resto de los tratamientos.(AU)

INTRODUCTION: Rheumatoid Arthritis (RA) is a chronic disease, very common in women, characterized by polyarticular and symmetrical inflammation with potential systemic involvement. Its prevalence in Argentina is 2 every 1,000 subjects; it is a cause of employment disability and of significant increase in mortality. To treat this condition, several conventional drugs -called disease-modifying anti-rheumatic drugs (DMARDs)- are used, methotrexate being the first choice. In case of inadequate response or intolerance to these drugs, the use of biological agents is recommended, including TNF-alpha inhibitors (anti-TNFs), or other biological agents such as tocilizumab. TECHNOLOGY: Tocilizumab is a humanized monoclonal antibody, interleukin-6 (IL- 6) receptor inhibitor. It was approved by the FDA, EMA and ANMAT to treat moderate to severe RA with inadequate response or intolerance to one or more conventional DMARDs or anti-TNF. It is administered intravenously at 8 mg/kg/monthly doses. PURPOSE: To assess the available evidence on the efficacy, safety and coverage related aspects regarding the use of tocilizumab in patients with RA. METHODS: A bibliographic search was carried out on the main literature databases: DARE, NHS EED, MEDLINE, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews (SR); controlled, randomized clinical trials (RCTs); health technology assessments (HTA) and economic evaluations (EE); clinical practice guidelines (CPG) and coverage policies of other health systems. RESULTS: One direct and two indirect meta-analyses, one RCT, three CPGs, two HTAs and twelve coverage policies were included in the report. Their main results are described below. Tocilizumab versus DMARDs One meta-analysis published in 2013 (which included fifteen RCTs comparing tocilizumab with any DMARD, including a total of more than 5,500 patients) demonstrated tocilizumab efficacy in patients who were DMARD-naive, failed prior to DMARD or anti-TNF therapy showed an ACR (composed index evaluating the disease activity improvement compared to baseline) 20, 50 and 70 significantly higher response in tocilizumab treated patients than in control groups at Week 24, as well as a significant difference in radiologic progression decrease favoring it. Three of the studies assessed monotherapy (tocilizumab vs. DMARD) and in the rest, tocilizumab with one DMARD (generally methotrexate) was compared versus a DMARD alone. Tocilizumab versus other biological agents : The only RCT published compared tocilizumab monotherapy versus adalimumab (325 patients) in subjects whom methotrexate treatment continuation was inadequate. It showed a significantly high decrease in DAS 28 (composite index to assess clinical response) in the tocilizumab arm. One 2012 indirect meta-analysis (including more than 16,000 patients), analyzed the efficacy of different biological agents combined with DMARDs in patients who failed standard DMARDs, and did not find significant differences in the responses of ACR 20, 50 and 70 responses between etanercept and tocilizumab. Another indirect meta-analysis published in the same year (1,873 patients) found similar ACR 20, 50 and 70 responses between tocilizumab and other biological agents, in subjects who failed an anti-TNF. The European and Argentinean CPGs from 2013, consider the use of biological therapies adequate, including tocilizumab as an alternative, in patients who failed or were intolerant to a previous DMARD or anti-TNF therapy. The European guidelines also recommend it as an alternative in case of failed biological agents other than anti-TNF. The US GPCs (2012) recommend the indication of anti-TNF agents in patients with inadequate response to DMARDs; in case of failure to this second-line treatment changing to a biological therapy is recommended, being tocilizumab one of the choices. One UK HTA from 2012 that uses an economic evaluation, considers tocilizumab indication as an additional alternative to other biological agents in case of DMARD failure, as well as in the case of inadequate response to anti-TNF and rituxumab contraindication. One US HTA from the same year describes there is not enough evidence to support the superiority of one biological agent to the other. As regards coverage policies, eight US health sponsors cover tocilizumab only in case of failure to anti-TNF therapy failure while four also cover it in case of DMARD failure. CONCLUSIONS: There is high quality methodological evidence on the efficacy of tocilizumab therapy in patients with moderate to severe RA, however, there is not adequate evidence on its efficacy compared to other biological agents. Only one comparative study showed that in patients who cannot receive methotrexate, tocilizumab is clinically and statistically more efficacious as monotherapy when compared with adalimumab monotherapy, however, there are no other RCTs assessing its efficacy versus other biological agents, and studies based on indirect comparisons suggest that it is similar to etanercept. Some international guidelines consider its use as another alternative in case of inadequate response to DMARDs, other guidelines only consider it in case of anti-TNF or biological agent failure. In view of this, the decision regarding coverage will depend on the relative cost of tocilizumab versus the other therapies. (AU)

INTRODUÇÃO: A artrite reumatóide (AR) é uma doença cônica, mais frequente em mulheres, caracterizada por inflamação poliarticular e simétrica, com possível compromisso sistêmico. A prevalência na Argentina é de 2 para cada 1.000 habitantes. É causa de deficiência laboral e aumento significativo da mortalidade. Para seu tratamento, se utilizam diferentes fármacos tradicionais denominados drogas modificadoras da AR (DMAR), sendo o metotrexate a primeira eleição. Nos casos de resposta inadequada ou intolerância a esses medicamentos, recomenda-se o tratamento com agentes biológicos, incluindo os inibidores de TNF alfa (anti-TNF) ou outros agentes biológicos como o tocilizumab. TECNOLOGIA: O tocilizumab é um anticorpo monoclonal humanizado, inibidor do receptor da interleucina 6 (IL-6). Foi aprovado pela FDA, EMA e ANMAT para o tratamento da AR de moderada a severa com resposta inadequada ou intolerância a uma ou mais DMAR convencionais ou a anti-TNF. Administra-se em forma endovenosa em dose de 8 mg/Kg/mês. OBJETIVO: Avaliar a evidencia disponível sobre a eficácia, segurança e aspectos relacionados às políticas de cobertura do uso do tocilizumab em pacientes com AR. MÉTODOS: Realizou-se uma busca nas principais bases de dados bibliográficos DARE, NHS EED, em buscadores genéricos de Internet, agências de avaliação de tecnologias sanitárias e financiadores de saúde. Priorizou-se a inclusão de revisões sistemáticas (RS), ensaios clínicos controlados aleatorizados (ECAs), avaliações de tecnologias sanitárias (ATS) e econômicas (EE), guias de práticas clínica (GPC) e políticas de cobertura de outros sistemas de saúde. RESULTADOS: Incluíram-se no reporte uma metanálise direta e duas indiretas, um ECA, três GPC, duas ATS e doze políticas de cobertura. Descrevem-se os principais resultados. Tocilizumab comparado com DMARs: Uma metanálise publicada em 2013 (incluiu quinze ECAs que comparavam tocilizumab com algum DMAR, incluindo um total de mais e 5.500 pacientes) demonstrou a eficácia do tocilizumab em pacientes virgens de DMAR, com falha prévia a DMAR ou a anti-TNF, encontrando uma resposta ACR (índice composto que avalia a melhora da atividade da doença com relação ao nível basal) 20, 50 e 70 na semana 24, significativamente superior nos pacientes tratados com tocilizumab que nos grupos controles, assim como uma diferença significativa na redução da progressão radiológica a favor do mesmo. Três dos estudos avaliavam a monoterapia (tocilizumab vc DMAR) e os demais compararam tocilizumab com um DMAR (usualmente metotrexane) versus somente DMAR. Tocilizumab comparado con otros agentes biológicos: O único ECA comparou a monoterapia com tocilizumab versus adalimumab (325 pacientes) em sujeitos nos que fosse inapropriado continuar tratamento com metotrexate. Mostrou uma redução significativamente superior do DAS 28 (índice composto para avaliar a resposta clínica) no ramo do tocilizumab. Uma metanálise indireta de 2012 (mais de 16.000 pacientes) analisou a eficácia de diferentes agentes biológicos combinados com DMAR em pacientes com falha a DMAR convencionais, não encontrando diferenças significativas nas respostas ACR 20, 50 e 70 entre etanercept e tocilizumab. Outra metanálise indireta publicada no mesmo ano (1.873 pacientes) encontrou respostas similares em ACR 20, 50 e 70 entre tocilizumab e outros agentes biológicos, em sujeitos com falha ao anto-TNF. Os GPC europeus e argentinos de 2013 consideram adequado o uso de terapias biológicas, entre as quais se encontra o tocilizumab como alternativa em pacientes com falha ou intolerância a um tratamento prévio com DMARs ou anti-TNF. Os GPC europeias também o recomendam como opção ante a falha à agentes biológicos diferentes ao anti-TNF. As GPC estadunidenses (2012) recomendam a indicação de agentes anti-TNF nos pacientes com respostas inadequadas a DMARs; nos casos de falha a essa segunda linha de tratamento recomenda-se mudar a terapia biológica, sendo uma das opções o tocilizumab. Uma ATS do Reino Unido, de 2012, que utiliza uma avaliação econômica, considera a indicação do tocilizumab como uma alternativa mais aos outros agentes biológicos ante a falha a DMARs, assim como ante a resposta inadequada a anti-TNF e contraindicação a rituximab. Uma ATS estadunidense do mesmo ano afirma que não há evidência suficiente que abale a superioridade de um agente biológico sobre outro. Em relação às políticas de cobertura, oito financiadores estadunidenses cobrem o tocilizumab somente em casos de falha ao tratamento com agentes anti-TNF, enquanto quatro também o contemplam em caso de falha aos DMARs. CONCLUSÕES: Existe evidencia de alta qualidade metodológica sobre a eficácia do tratamento com tocilizumab em pacientes com AR moderada a severa, porém não existe evidência adequada sobre a eficácia comparativa com outros agentes biológicos. Um único estudo comparativo mostrou que em pacientes que não podem receber metotrexate, tocilizumab é clínica e estatisticamente mais eficaz como monoterapia comparado à monoterapia com adalimumab, porém, não existem outors ECAs que hajam avaliado sua efetividade em relação a outros agentes biológicos e estudos baseados em comparações indiretas sugerem que é similar ao etanercept. Alguns guias internacionais contemplam seu uso como uma alternativa mais em caso de resposta inadequada a DMARs, outros guias somente ante a falha ao anti-TNF ou outros agentes biológicos. Frente a essa situação a decisão de cobertura dependerá do custo relativo do tocilizumab em relação aos demais tratamentos.(AU)