Tocilizumab In Rheumatoid Arthritis Research Articles

E035 Tocilizumab and the reversible cerebral vasoconstriction syndrome

Abstract Background/Aims Reversible cerebral vasoconstriction syndrome (RCVS) describes a group of conditions characterised by thunderclap headache and radiographic evidence of multifocal cerebral artery vasoconstriction. While typically following a benign course to resolution within a period of days to weeks, a small proportion of patients experience complications such as stroke, seizure or cerebral oedema. While a wide range of aetiological factors have been implicated in the clinical literature, there is, to our knowledge, only one prior publication reporting an association between tocilizumab and RCVS. Methods Here, we describe the case of a patient who developed RCVS following treatment with tocilizumab for rheumatoid arthritis. Results A 41 year old lady presented to her local emergency department after waking from sleep with sudden onset thunderclap headache with associated photophobia and vomiting. There was no prior history of headache. Her past medical history included rheumatoid arthritis and depression. At time of admission, her prescribed medications included folic acid, sertraline, methotrexate and tocilizumab. For the past 5 years, her rheumatoid arthritis had been controlled with a combination of methotrexate and etanercept, but, with her disease flaring, the etanercept was switched for tocilizumab six weeks prior to admission. Initial evaluation with CT head, CT venogram and lumbar puncture did not reveal any underlying abnormalities. A subsequent CT angiogram of the head and neck revealed multiple smooth stenoses bilaterally within the anterior cerebral arteries (ACA), middle cerebral arteries (MCA) and posterior cerebral arteries (PCA). A diagnosis of RCVS was made and tocilizumab was discontinued. Conclusion In patients taking tocilizumab, particular consideration should be given to the possibility of RCVS when performing a diagnostic evaluation of thunderclap headache. Tocilizumab may be an aetiological factor in this condition and its discontinuation may prevent the development of more serious complications. Disclosure B. Corney: None. C. Rhys-Dillon: None.

Improvement in joint inflammation is accompanied by reduction in arterial inflammation: Tocilizumab in rheumatoid arthritis

Improvement in joint inflammation is accompanied by reduction in arterial inflammation: Tocilizumab in rheumatoid arthritis

Bone-sparing effects of tocilizumab in rheumatoid arthritis: a monocentric observational study.

Bone loss is a common feature in several autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Indeed, the high levels of pro-inflammatory cytokines seem to enhance bone resorption and to diminish bone formation, thus producing an uncoupling between osteoclast and osteoblast function and favoring the onset of juxtarticular as well as systemic osteoporosis. Many papers underline the high prevalence of osteoporosis in RA, as well as the negative correlation between interleukin 6 (IL-6) serum levels and bone mineral density (BMD). The aim of this study was to assess the effectiveness of one-year treatment with tocilizumab (TCZ), the first approved IL-6 receptor inhibitor, in reducing bone loss in RA. We enrolled 18 patients fulfilling 2010 ACR and EULAR criteria for RA from our arthritis outpatient clinic, assessing clinical and biochemical parameters during a 12-month period. The patients received TCZ 8 mg/kg i.v. every 4 weeks and underwent dual energy X-ray absorptiometry (DXA) for the measurement of bone mineral density (BMD) at baseline and at the end of study. Serum levels of C-reactive protein (CRP), erythrocytes sedimentation rate (ESR), IL-6, serum CrossLaps, osteoprotegerin (OPG), receptor activator of nuclear factor κβ ligand (RANK-L) and dickkopf-1 (DKK-1) were measured at baseline, at 6 months and 1 year. No significant difference in IL-6, RANK-L, DKK-1, OPG and serum CrossLaps levels between baseline, 6 months and 1 year were found. A significant increase of lumbar spine BMD was evidenced after 1 year of TCZ treatment. No difference in total body and femoral neck BMD was documented the end of the study. This study suggest the bone-sparing effect of TCZ in RA affected individuals.

Genetic Biomarkers as Predictors of Response to Tocilizumab in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Rheumatoid arthritis (RA) is a lifelong, debilitating disease which incredibly impacts a patient’s quality of life if not treated to the optimal target. The clinical response of tocilizumab, an interleukin-6 (IL-6) inhibitor, is associated with several gene polymorphisms, particularly targeting the IL-6 pathway. This systematic review and meta-analysis seeks to investigate genetic biomarkers that predict the treatment outcome of tocilizumab therapy in RA patients. After evaluating the quality of retrieved records, five studies were chosen to carry out a quantitative synthesis involving 591 participants. We analysed genetic markers of IL-6R single nucleotide polymorphism (SNP)s rs12083537, rs2228145 and rs4329505, FCGR3A, CD69, GALNT18 and FCGR2A. A plausible finding based on meta-analysis revealed that RA patients with homozygous AA genotype for rs12083537 polymorphism of the IL-6R gene demonstrate a better response to TCZ treatment as opposed to homozygous and heterozygous patients with the G allele. Nonetheless, limitations in evaluating the available studies by meta-analysis include a lack of studies with dissimilarities in study design and outcome definitions, small sample sizes with low statistical power and heterogeneity of cohorts, a restricted the number of tested SNPs and small effects for the selected variants. Inconsistent finding remains as a great challenge to forge ahead towards personalised medicine for RA management.

Successful combined treatment with omalizumab and tocilizumab in a case of chronic spontaneous urticaria and rheumatoid arthritis: A case report and literature review

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody used to treat uncontrolled chronic spontaneous urticaria (CSU). Sometimes patients with CSU also have other autoimmune conditions. Recent studies have demonstrated the safety and efficacy of a combination treatment with omalizumab and other biologics. Here, we report the first successful treatment with omalizumab for CSU and tocilizumab for rheumatoid arthritis. Since omalizumab is unlikely to cause severe immunosuppression, it may be a treatment option for CSU, even in patients treated with other biologics.

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Cases of eosinophilia in patients treated with Tocilizumab for rheumatoid arthritis

Hypereosinophilia is a haematological complication that can lead to severe organ damage. This article describes 2 patients who presented eosinophilia under treatment with tocilizumab for rheumatoid arthritis. We will describe the evolution of eosinophilia over time, with the monitoring of medication and discuss the potential link with the treatment as well as the importance of this manifestation in the context of the disease.

COVID-19 PNEUMONIA COMPLICATED BY CMV PNEUMONITIS FOLLOWING TREATMENT WITH AN IL-6 INHIBITOR

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: IL-6 inhibitors have emerged as a treatment option for moderate to severe COVID-19 infections. A hyperinflammatory state has been theorized to be the driving factor for acute respiratory distress syndrome in COVID-19. We discuss the case of a patient who received sarilumab for severe Covid infection and later developed CMV pneumonitis. IL- 6 inhibitors have been associated with secondary bacterial infections;however, the data on secondary viral and atypical infections are limited. CASE PRESENTATION: A 55-year-old male with no known past medical history presented to the hospital with complaints of worsening cough and shortness of breath. The patient was found to be COVID positive 3 days prior to presentation. CT chest on admission showed extensive peripheral ground-glass and consolidative lung opacities. Treatment with Decadron and Remdesivir was initiated.On hospital day 9, the patient had worsening respiratory status requiring up to 40 liters of vapotherm at 100% FiO2. After ruling out superimposed bacterial infection, he was treated with Sarilumab 400mg for worsening acute hypoxemic respiratory failure felt to be due to a hyperimmune syndrome from COVID-19. 10 days following treatment with Sarilumab, the patient's CRP normalized and his oxygen requirement decreased, he eventually weaned down to 5L nasal cannula.On hospital day 27, the patient again developed acute respiratory distress requiring intubation. A repeat chest CT showed evolving ground-glass and consolidative opacities with new basilar predominant traction bronchiectasis and architectural distortion. Additional lab testing revealed, CMV IgG >10 ( 0.00-0.59 U/ml) CMV IgM of 37.2 (0.0-29.9 AU/ml), CMV PCR DNA of 325000 ( not detected), and negative fungitell. Samples from bronchoalveolar lavage showed a CMV PCR of 46500 IU/ml ( not detected). Treatment with ganciclovir 5mg/kg q12h was initiated. Following treatment, the patient had progressive improvement in respiratory status, was weaned from the ventilator, and eventually discharged from the hospital. DISCUSSION: Cytokine storm is thought to play a key role in the lung injury seen in COVID 19 and IL-6 is essential in the propagation of cytokine Storm. There is an ongoing concern for bacterial infections in the setting of IL-6 inhibitors but the data on viral infections in this setting is limited. Van Duin et al describes a case of CMV reactivation in the setting of treatment with tocilizumab for rheumatoid arthritis. The patient developed fever and shortness of breath following the 2nd infusion of tocilizumab. A CT scan of the chest showed pneumonitis. Labs were significant for viremia on CMV PCR and positive CMV IgG. The patient had improvement after treatment with ganciclovir, similar to our case. CONCLUSIONS: The adverse effects of IL-6 inhibitors are not fully understood. Based on our limited experience we recommend checking CMV IgG before initiation of IL-6 inhibitors. REFERENCE #1: Han, Q., Guo, M., Zheng, Y., Zhang, Y., De, Y., & Xu, C. et al. (2020). Current Evidence of Interleukin-6 Signaling Inhibitors in Patients With COVID-19: A Systematic Review and Meta-Analysis. Frontiers In Pharmacology, 11. doi: 10.3389/fphar.2020.615972 REFERENCE #2: Tleyjeh, I., Kashour, Z., Damlaj, M., Riaz, M., Tlayjeh, H., & Altannir, M. et al. (2021). Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. Clinical Microbiology And Infection, 27(2), 215-227. doi: 10.1016/j.cmi.2020.10.036 REFERENCE #3: van Duin D, Miranda C, Husni E. Cytomegalovirus viremia, pneumonitis, and tocilizumab therapy. Emerg Infect Dis. 2011;17(4):754-756. doi:10.3201/eid1706.101057 DISCLOSURES: No relevant relationships by Gretel D'Souza, source=Web Response No relevant relationships by Elizabeth Pandian, source=Web Response

PREVOTELLA BIVIA BACTEREMIA POST TOCILIZUMAB IN A PATIENT WITH SEVERE COVID-19 PNEUMONIA

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Anaerobes generally constitute a major component of the gut microbiome. They play a significant role in the pathogenesis of infections following disruption of mucosal integrity. Anaerobic organisms are usually difficult to grow and identify and hence may often be overlooked. We present a patient with severe COVID-19 pneumonia who developed de-novo Prevotella bivia bacteremia, following tocilizumab. CASE PRESENTATION: A 38 year old Caucasian male with morbid obesity and no other past medical history presented to the emergency department with complaints of cough, fever, chills and poor appetite for the past 10 days. Upon arrival, he was profoundly hypoxic with Spo2 70% on ambient air. He tested positive for COVID-19. On physical examination, his BMI was 62 kg/m2, he was febrile, in moderate respiratory distress, cardiopulmonary examination revealed coarse bilateral breath sounds. His physical examination was otherwise unremarkable. His chest radiograph demonstrated hazy opacification in both mid lungs and left lung base suggestive of multifocal pneumonia. CT chest did not reveal evidence of pulmonary embolism. Lower extremity ultrasound was however negative for a DVT. Laboratory findings was significant for elevated C-reactive protein 12.4 mg/dl. Patient was placed on heated high flow nasal cannula and received dexamethasone and tocilizumab. His respiratory status continued to worsen and he was subsequently intubated. Lower respiratory culture was positive for MSSA and patient was started cefepime and vancomycin was added as he clinically continued to decompensate. Within the next week, blood culture was positive for Prevotella bivia and his antibiotic regimen was changed to pipericillin-tazobactam. Repeat blood culture continued to be positive and this time, for Enterococcus faecalis. The antibiotic regimen was further changed to meropenem. Interestingly, on his physical examination, there was no abnormalities on his abdomen or pelvic area. CT abdomen pelvis did not shows any acute abnormalities. Following meropenem initiation, his subsequent blood cultures have been negative for any growth. Patient remains intubated with a guarded prognosis. DISCUSSION: Prevotella bivia is one of several species of bacteria in the genus Prevotella. It is an anaerobic gram negative organism that is found in the oral, vaginal, and gut microbiome. Some of the infections caused by this organism include aspiration pneumonia, lung abscess, otitis media, and sinusitis. Various species of Prevotella have been isolated from abscesses and burns close of the mouth, bite, paronychia, urinary tract infection, brain abscess, osteomyelitis, and bacteremia when there is an associated respiratory tract infections. Prevotella bivia bacteremia is highly uncommon. CONCLUSIONS: As we continue to learn more about COVID-19 infection and its treatment modalities, we may come across such unusual scenarios. REFERENCE #1: 27.Curtis JR, Perez-Gutthann S, Suissa S, et al. Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. Semin Arthritis Rheum 2015;44:381. REFERENCE #2: Yanagisawa M, Kuriyama T, Williams DW, Nakagawa K, Karasawa T. Proteinase activity of prevotella species associated with oral purulent infection. Curr Microbiol. 2006;14(5):375–378. doi: 10.1007/s00284-005-0261-1 REFERENCE #3: Metronidazole Resistance in Prevotella spp. and Description of a New nim Gene in Prevotella baroniaeC. Alauzet, F. Mory, C. Teyssier, H. Hallage, J. P. Carlier, G. Grollier, A. Lozniewski DISCLOSURES: No relevant relationships by Alfred Aiyanyor, source=Web Response No relevant relationships by Navitha Ramesh, source=Web Response No relevant relationships by Q. Kamran Uddin, source=Web Response

The Effect of Tocilizumab on Inflammatory Markers in Patients Hospitalized with Serious Infections. Case Series and Review of Literature.

Background: The human anti-IL-6 receptor antibody tocilizumab (TCZ) has been approved for the treatment of rheumatoid arthritis (RA) and giant cell arteritis (GCA). It is observed that CRP levels drop quickly after starting TCZ treatment. This may lead to misinterpretation of laboratory results when accessing the patient with infectious disease while on TCZ. We conducted this study to report cases treated with tocilizumab who developed serious infections with special reference to levels of CRP and to review the literature on the effect of tocilizumab on acute phase response (APR) during infections. Methods: The files of RA and GCA patients hospitalized in the Tel Aviv medical center between 2009–2019 were reviewed. Cases of patients with RA and GCA treated with tocilizumab who were hospitalized due to severe infections were reviewed with special emphasis on the duration of treatment, type of infection, and APR. Results: We identified nine admissions. Seven patients were treated with tocilizumab for RA, two for GCA. The diagnosis was pneumonia in three cases, osteomyelitis in one, cellulitis in one, endocarditis due to Whipple disease in one, abscess of cervix uteri in one, meningitis in one, and perforated diverticulitis in one. The mean CRP levels on admission were 4.75 mg/L (normal range, up to 5 mg/L). All cases were diagnosed correctly on admission. Conclusions: CRP levels may not correctly reflect the severity of infectious diseases during tocilizumab treatment. Increased awareness of the masking effect of tocilizumab on the APR during infection is needed in order to avoid a delay in the diagnosis.

Multiplex analysis of laboratory biomarkers in assessing effectiveness of tocilizumab in treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune rheumatic disease of unknown etiology, characterized by chronic erosive arthritis (synovitis) and that can involve other tissues and organs. The use of biologics in clinical practice, including humanized monoclonal antibodies (IgG1) to interieukin-6 (IL-6R) receptors, it's the cause to search for predictors of response to this therapy. The aim of this study was to determine the relevance of multiplex cytokine analysis in evaluating the effectiveness of tocilizumab (TCZ) in RA. Materials and methods . We examined serum samples from 43 patients with RA. The comparison group was 297 healthy subjects matched by gender and age. Serum concentration of IgM and IgA rheumatoid factors (RF) and C-reactive protein (CRP) in serum was measured by immunonephelometry; of antibodies to cyclic citrullinated peptide (anti-CCP), antibodies to modified citrullinatedvimentin (anti-MCV), matrix metalloprotinase-3 (MMP-3) - by enzyme-linked immunosorbent assay; of cytokines - by xMAP technology. Results. At week 4 on TCZ therapy, patients with RA had a decrease serum levels of CRP, IgM RF, AMCV, MMP-3; on 8th - ESR, CRP, IgM and IgA RF, anti-CCP and anti-MCV, on the 24th - of all biomarkers, excluding anti-CCP. At 4th, 8th, 24th weeks of therapy, there was a decrease in serum levels of all studied cytokines (excluding IL-6 at 4th week and IL- 1ra at 8th and 24th weeks). The most associated factors witch effectiveness of TCZ are: MMP-3 (AUC0.7), anti-CCP (0.7) and VEGF (0.7). A predictive model based on the assessment of serum levels of this biomarkers can predicting the clinical response to TCZ in RA (AUC = 0.85; CI: 0.7-1.0). Conclusion. The data about association of basal serum concentrations of anti-CCP, MMP-3 and VEGF with the response in RA patients, made it possible to create a multiparameter index for predicting the TCZ effectiveness.

Gastrointestinal Perforation in a COVID-19 Patient

To the Editor Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), the virus responsible for coronavirus disease-19 or “COVID-19,” is currently implicated in a global pandemic. As of April 19, 2020, there have been 2,241,778 confirmed cases worldwide.1 Although the pathophysiology is still being elucidated, there is evidence of hyperactivation of effector T cells and excessive release of inflammatory cytokines, particularly interleukin (IL)-6, leading to cytokine release syndrome and end organ damage.2 Current proposed treatments include tocilizumab, an IL-6 receptor antagonist, and corticosteroids. We present a brief case of a patient with COVID-19 who subsequently developed a gastrointestinal (GI) perforation, which we believe was due to the underlying disease process itself, or treatment modalities given. A 73-year-old man, with a prior history of coronary artery disease, peripheral vascular disease, diabetes, chronic kidney disease, and obesity (with a body mass index of 32), presented to the hospital with fever, cough, and shortness of breath. On presentation, he was febrile and hypoxemic requiring a non-rebreather at 15 L/min. Initial blood work showed a white blood cell count of 22.0 × 103/μL, hemoglobin of 11.6 g/dL, hematocrit of 34%, platelet count of 257 × 103/μL, Na of 132 mEq/L, K of 4.6 mEq/L, Cl of 104 mEq/L, CO2 of 10 mEq/L, BUN of 92 mg/dL, and Cr of 4.0 mg/dL (with a known baseline of 1.8 mg/dL). Chest x-ray revealed diffuse, patchy, bilateral lung opacities. Nasal polymerase chain reaction swab for SARS-CoV-2 was positive. On hospital day 2, he required intubation and mechanical ventilation. Also, on hospital day 2, he received tocilizumab, 400 mg intravenously. Because of the failure of ventilator weaning, he underwent a tracheostomy on hospital day 9. He received intravenous methylprednisolone, at a total daily dose of 100 mg, between hospital days 11 and 16, given his respiratory status had not significantly improved. By hospital day 16, he was still requiring full ventilatory support via his tracheostomy. He otherwise did not appear to have any other specific complaints. That day, a routine chest x-ray showed substantial subphrenic air likely representing a GI perforation, which was confirmed on a lateral decubitus film (Fig. 1). He was evaluated by surgery, and exploratory surgery was discussed; however, due to his high-risk surgical status, a conservative approach was chosen. He was followed up with serial abdominal examinations and given intravenous antibiotics. Six weeks later, he continues to do well and has since been decannulated. On review of his case, it was felt that either his underlying viral infection or his treatments (tocilizumab and/or corticosteroids) were the likely etiology of his perforation.FIGURE 1: Lateral abdominal decubitus XR with abdominal free air.SARS-CoV-2 represents a significant and ongoing cause of morbidity and mortality worldwide. This viral infection often presents with fever, cough, and shortness of breath, though GI symptoms, such as nausea, vomiting, abdominal pain, and diarrhea, are also common.3 Angiotensin-converting enzyme-2 receptor is a major functional receptor of SARS-CoV-2 and is expressed on the surface cells of the digestive tract, likely leading to the GI symptoms seen in the disease.3 To date, there have been no reports of GI perforation specifically attributed to SARS-CoV-2, though given the widespread expression of angiotensin-converting enzyme-2 receptors in the digestive tract, it is plausible that viral binding can lead to disruption of mucosal cell integrity. However, both tocilizumab and corticosteroids have been implicated in general GI perforation. Tocilizumab is associated with a small risk of GI perforation. On review of patients taking tocilizumab for rheumatoid arthritis, a GI perforation rate of 1.55 to 1.9 per 1000 patient years was seen.4 Mesenteric adipose tissue is both maintained by and a major source of IL-6, and although IL-6 activity leads to transmural inflammation of the bowel, the local accumulation of the adipose tissue itself can be protective against perforation. Thus, the inhibition of IL-6 by tocilizumab and the resulting breakdown of mesenteric fat are possible mechanisms of perforation.5,6 The IL-6 and cytokine release syndrome may have led to mucosal breakdown in our patient, and as he had a body mass index of 32 and likely increased mesenteric fat, he could have been more susceptible to tocilizumab's actions as well. Corticosteroids are also well known to lead to GI perforation. Corticosteroids can impair the body's ability to contain microperforations via anti-inflammatory properties, and also inhibit prostaglandin production, which has an important role in maintaining colonic mucosal integrity via secretion of mucin and bicarbonate.7 Ultimately, though the etiology of our patient's GI perforation is unclear, we hypothesize that it must be related to either his underlying disease process or is a consequence of treatment. Clinicians must remain aware of this potential complication when caring for COVID-19 patients. Lydia M. Winnicka, MDMangalore A. Shenoy, MD Department of Pulmonary and Critical Care Medicine NYU Winthrop Hospital, Mineola, NY [email protected]

Individual therapeutic DAS28-dcrit responses differentiate between effectiveness of rheumatoid arthritis therapies and reflect patient-reported outcomes: retrospective analysis of DAS28 responses in comparative tocilizumab studies

Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p < 0.0001). DAS28-dcrit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.

Exposure-response modeling of tocilizumab in rheumatoid arthritis using continuous composite measures and their individual components.

Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures. Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6weeks, RSE: 24%) and the need for higher serum drug concentration (EC50 : 4.60μg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3weeks, RSE 19%; EC50 : 0.878μg/mL, RSE: 41%, IIV: 238%). Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.

Serious infections with tocilizumab in rheumatoid arthritis

Serious infections with tocilizumab in rheumatoid arthritis

Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

ObjectivesThis post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use.MethodsTOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety.ResultsOf 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups.ConclusionThe incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles.Trial RegistrationClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616.

PREDICTION OF TOCILIZUMAB AND RITUXIMAB EFFECTIVENESS IN RHEUMATOID ARTHRITIS

Objective: to study the possibility of prediction of treatment effectiveness with tocilizumab and rituximab in rheumatoid arthritis (RA), taking into account the clinical and immunological characteristics of patients. Material and methods. The efficacy of treatment with tocilizumab in 53 patients and rituximab in 22 patients with RA within 12 months was analyzed, the prognostic role of the initial values of activity indices, the presence of systemic manifestations, the duration of RA, levels of autoantibodies and acute phase proteins was evaluated. Results. The high efficacy of treatment with biological drugs in RA was established, the treatment goals were achieved by 84.91% of patients in the group of tocilizumab and 72.72% in the group of rituximab, but the remaining patients did not reach the treatment goal after 12 months of follow-up. Conclusions. Reliable predictors of a good response to tocilizumab in RA may be high activity of the joint syndrome, rituximab – seropositive variant of RA, as well as the presence of systemic manifestations.

Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK real-world, open-label study.

ObjectiveThe ACT-MOVE study assessed the real-world efficacy and safety of s.c. tocilizumab (TCZ-SC), provided as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 1 year, in patients with RA and an inadequate response to csDMARD therapy and/or first TNF inhibitor.MethodsIn this UK multicentre, open-label phase IIIb study, patients received TCZ-SC 162 mg once weekly for 52 weeks as monotherapy or with csDMARDs. Efficacy and safety were evaluated at baseline, weeks 2 and 4 and every 4 weeks thereafter up to week 52.ResultsOf 161 patients who received at least one dose of TCZ-SC, 21 (13.0%) received TCZ-SC alone and 140 (87.0%) TCZ-SC with a csDMARD(s). From baseline to week 52, there was a mean decrease in DAS28-ESR score among all patients (−3.68), and within monotherapy (−3.75) and combination therapy (−3.67) groups. The proportion of patients who achieved DAS28 clinical remission (DAS28-ESR <2.6) at week 52 was 75.4% (95% CI 66.8, 82.8). At the same time point, ≥80% of patients who remained on TCZ-SC achieved DAS28 clinical remission or had low disease activity (DAS28-ESR ≥2.6 and ≤3.2). Overall, 6.2% of patients had at least one serious adverse event (10.2/100 patient-years), and there was one death; 11.2% of patients discontinued owing to adverse events.ConclusionTCZ-SC was effective and tolerated in a real-world setting over 1 year. The efficacy of TCZ-SC was similar whether given as monotherapy or with csDMARDs; its safety profile was consistent with that previously established.Trial registrationClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02046603.

New insights and long-term safety of tocilizumab in rheumatoid arthritis.

Rheumatoid arthritis is a leading musculoskeletal cause of disability in Western society. Therapeutic options have expanded rapidly with the advent of biological agents as treatment options. One of these, tocilizumab, targets the interleukin-6 receptor and has been approved since the late 2000s in many jurisdictions. This approval was based on 6-12 month trials. It is now appropriate to look at longer-term studies and what new insights they have provided into this agent. Data are based largely on observational studies with their well-known limitations as well as some further randomized trials and provide a number of important observations regarding both efficacy and safety. In conclusion, the longer-term data suggest tocilizumab efficacy increases over time for both signs and symptoms and radiographic change. It is also corticosteroid sparing. The safety data are consistent with the shorter-term trials and are largely reassuring but some questions still remain over cardiovascular safety and cancer risk.

Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries.

Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries.