Anomalous Origin of a Right Coronary Artery from the Pulmonary Artery in a Middle-Aged Woman.

A 53-year-old female patient presented for evaluation of a murmur. The examination revealed a 2/6 systolic ejection murmur in the left upper sternal border. Transthoracic echocardiography with color Doppler showed increased blood flow around the apex of the right ventricle. Further imaging revealed the right coronary artery emerging from the pulmonary artery. (Level of Difficulty: Beginner.).

Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. METHODS: This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. RESULTS: By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. CONCLUSION: The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.

Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): A nested case-control analysis.

OBJECTIVE: Giant cell arteritis (GCA) is an inflammatory vasculitis preferentially affecting large and medium-sized arteries. High-dose oral glucocorticoids (GCs) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink (CPRD), we examined the risk of oral GC-related serious adverse events (SAEs) in a UK population of patients with giant cell arteritis (GCA). METHODS: We conducted a series of nested case-control analyses in GCA patients to examine the effect of increasing dose of prednisolone on the risk of developing diabetes, glaucoma, osteoporosis, fractures, serious infection requiring hospitalization, and death. We used conditional logistic regression to calculate the unadjusted and multivariate odds ratios (ORs) with 95% CIs for the associations between prednisolone use and the risks of all outcomes of interest. We stratified the analyses by increasing cumulative prednisolone use and average daily dose. RESULTS: In the multivariate analyses, we observed a trend of increasing risk of diabetes and osteoporosis with increasing cumulative dose of oral prednisolone (ptrend < 0.05). GCA patients in the highest daily dose category (30mg/d) had an increased risk of diabetes (adjusted OR, 95% CI) (4.7, 2.8-7.8), osteoporosis (1.9, 1.2-2.9), fractures (2.6, 1.6-4.3), glaucoma (3.5, 2.0-6.1), serious infection (3.3, 2.2-5.2), and death (2.1, 1.3-3.5) compared to those with lower average daily prednisolone doses (5mg/d). CONCLUSION: Compared to lower average daily prednisolone doses, high average daily doses were associated with an increased risk of serious adverse effects.

Incidence of outcomes potentially associated with corticosteroid therapy in patients with giant cell arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is an inflammatory disorder of blood vessels that preferentially affects large- and medium-sized arteries. High-dose oral corticosteroids (CS) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink, we quantified and compared the incidence of selected potentially CS-associated adverse outcomes in patients with and without GCA. METHODS: We conducted a retrospective follow-up study of GCA and non-GCA patients to examine the incidence of adverse outcomes attributable to CS use. Eligibility criteria for the GCA group included a first-time diagnosis of GCA at age 50 years or older with receipt of ≥1 prescription(s) for prednisolone. GCA patients were matched to a GCA-free comparison group of equal size on age, sex, general practice, and calendar time. We estimated incidence rates and incidence rate ratios (IRRs) for diabetes, osteoporosis, glaucoma, fractures, serious infection requiring hospitalization, and death for GCA and non-GCA patients and compared all-cause hospitalizations between the two groups. RESULTS: The cohort consisted of 5011 GCA and 5011 matched non-GCA patients. Approximately 74% were women, and mean age at GCA diagnosis was 72.9 years. The IR for all outcomes was greater in the GCA group than the non-GCA group. IRRs [95% confidence intervals (CIs)] were as follows: diabetes 1.4 (1.2-1.7), osteoporosis 2.4 (2.1-2.8), fractures 1.4 (1.2-1.6), glaucoma 2.0 (1.6-2.5), serious infection requiring hospitalization 1.5 (1.3-1.7), and death 1.2 (1.0-1.3). CONCLUSION: Compared with age- and sex-matched non-GCA patients, patients with GCA were at increased risk for diabetes, osteoporosis, fracture, and glaucoma and at a marginally increased risk for death.

An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy.

OBJECTIVE: To evaluate associations between lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity, at baseline and during treatment, with the risk of major adverse cardiovascular events (MACE) in tocilizumab-treated patients with RA. METHODS: In retrospective post hoc analyses, data were pooled for 3,986 adult patients with moderate to severe RA who received ≥1 dose of tocilizumab (4 mg/kg or 8 mg/kg) intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations between baseline characteristics and posttreatment changes in laboratory and disease characteristics (week 24) and change in disease activity and laboratory values from baseline to week 24 with the risk of future MACE during extended followup. RESULTS: We identified 50 independently adjudicated cases of MACE during 14,683 patient-years of followup (0.34 MACE cases/100 patient-years). At baseline, age, a history of cardiac disorders, the Disease Activity Score in 28 joints (DAS28), and the total cholesterol:high-density lipoprotein cholesterol ratio were independently associated with MACE in multivariable models (P < 0.05 for all). During treatment, a higher DAS28 and higher swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in the DAS28 and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with the risk of MACE. CONCLUSION: In this population of patients treated with tocilizumab, an association was observed between the baseline total cholesterol:high-density lipoprotein cholesterol ratio and an increased risk of MACE. The risk of MACE while receiving treatment, however, was associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings.

Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics.

INTRODUCTION: Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood. METHODS: We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy. RESULTS: We documented evidence for four major phenotypes of RA synovium - lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004). CONCLUSIONS: These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT01119859

Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial.

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.