Une progression tumorale fulgurante sous abatacept

IntroductionCo-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA).ObservationWe herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma.DiscussionAlthough no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.     

Improvement in insulin resistance after short-term treatment with abatacept: case report and short review

Insulin resistance, a key feature of type 2 diabetes, is an independent risk factor for developing cardiovascular diseases (CVD), and represents the core of metabolic syndrome (MetS). Actually, an intriguing correlation between MetS and inflammation associated with rheumatoid arthritis (RA) is largely accepted but not yet completely clarified in detail. Recently, the therapeutic arsenal against RA has been enriched of abatacept, a fusion protein (CTLA4 immunoglobulin) designed to modulate the T cell co-stimulatory signal mediated through the CD28–CD80/86 pathway. Here, we report a case of dramatic improvement in insulin resistance, estimated with the surrogate measure HOMA-IR, after treatment with abatacept. Lastly, we shortly review the preclinical evidences supporting a possible role of T lymphocytes in rheumatoid arthritis-associated insulin resistance and how abatacept could improve glucose metabolism by suppressing adipose tissue infiltrating cells.     

The development of erythema elevatum diutinum in a patient with juvenile idiopathic arthritis under treatment with abatacept

In this case report, we present the first report of erythema elevatum diutinum after treatment of juvenile idiopathic arthritis with abatacept. Although it could also be coincidental, in our case, the appearance of vasculitis was not blocked by the simultaneous administration of a stimulation inhibitor, and alerts to the fact that as effective as a abatacept may be to control of the inflammatory articular symptoms, this might not translate into control of the disease.     

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study

OBJECTIVE: To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving > or =1 traditional nonbiologic and/or biologic disease-modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study. METHODS: This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo. RESULTS: The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7-12.5%). CONCLUSION: Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.     

Improved rheumatoid digital vasculitis in a patient treated with TNFα agent blocking (infliximab)

Rheumatoid vasculitis (RV) is an uncommon but potentially catastrophic complication of rheumatoid arthritis (RA). There are few current extensive studies and no consensus regarding the clinical, laboratory, histologic features and management or prognosis of RV. We report a case of RV in a 74-year old woman with a long (14 years) history of RA, who developed vasculitis of distal arteries with gangrene of digits of upper and lower extremities. After the failure of various immunosuppressive drugs (cyclophosphamide, methotrexate), the patient was treated with anti-TNFalpha infliximab. Digital gangrene healed within four months from the start of anti-TNFalpha treatment.     

Dynamic Pulmonary Artery Obstruction Causing Right Ventricular Failure after Cardiac Transplantation in a Patient with Mustard–Senning Corrected d‐Transposition of the Great Arteries

Patients with congenital d‐transposition of the great arteries (d‐TGA) undergoing palliative atrial baffle surgery in infancy often develop systemic ventricular failure in adulthood. If they undergo cardiac transplantation, they are prone to morphologic right ventricular (RV) failure secondary to severe pulmonary hypertension as a result of systemic ventricular failure. We report a case of a patient with d‐TGA and biventricular ventricular failure requiring heart transplantation (HT) that developed RV failure postoperatively because of dynamic pulmonary artery (PA) obstruction at the anastomotic site of PA. Obstruction at the site of PA anastomosis due to torsion or redundancy of the donor or recipient PA is a rare but treatable cause of postoperative RV failure. In this case, rapid identification of the etiology of RV failure and implementation of corrective therapies before the development of end‐organ dysfunction, resulted in complete RV recovery and normal allograft function. This case represents the first known report of dynamic PA anastomoticobstruction resulting in RV failure after HT that was corrected with pulmonary arterioplasty, and RV assist device resulting in complete recovery.     

Immunohistological analysis of synovium treated with abatacept in rheumatoid arthritis

The aim of this study was to investigate the histological changes following the treatment with abatacept compared with methotrexate (MTX) by an immunohistological examination of synovial tissue for eleven different molecules to detect the expression patterns of cytokines. We histologically assessed the synovial tissues from 10 methotrexate (MTX)-treated RA patients as controls and 5 abatacept plus MTX-treated RA patients. The synovium samples from both group were assessed by hematoxylin and eosin (HE) staining and analyzed for their expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD20, CD68, vascular endothelial growth factor (VEGF), CD4, CD8, CD28, CD80, and CD86 by an immunohistological examination. HE staining showed that there was a decrease in cell proliferation in the synovium of the RA patients who received abatacept compared with the controls. TNF-α, IL-6, and VEGF were not significantly different in either of the groups. On the other hand, MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 were significantly decreased in the abatacept group compared with the control (P < 0.05). Based on the histological analysis of the synovium, it appears that the efficacy of the treatment with abatacept may involve the inhibition of cell proliferation, with decreases in the expression of MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 in the synovium. These findings indicate inhibition of not only T cells but also B cells and macrophages, which likely plays a role in the efficacy of abatacept in RA patients.     

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial

OBJECTIVE: To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy. METHODS: This was a 12-month, multicenter, randomized, double-blind, placebo-controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial. RESULTS: A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. CONCLUSION: Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.     

Whipple's disease-associated pulmonary hypertension with positive vasodilator response despite severe hemodynamic derangements

Pulmonary hypertension (PH) associated with Whipple's disease (WD-PH) is extremely rare, and the underlying pathophysiological processes are incompletely understood. Alterations in hemodynamics can be severe, with right ventricular (RV) dysfunction being common. A case involving a 23-year-old man with WD-PH who exhibited a dramatic vasodilator response during right heart catheterization despite severely altered pulmonary hemodynamics and concomitant RV dysfunction is reported. While the patient's symptoms responded poorly to treatment with nifedipine and sildenafil, significant improvement in dyspnea, RV dysfunction and pulmonary pressures were noted following antibiotic therapy. The present report highlights that despite severely elevated pulmonary artery pressures and RV dysfunction in WD-PH patients, a highly significant vasodilator response and dramatic improvement with antibiotic therapy may be observed. Furthermore, the case highlights the phenomenon of PH in the setting of inflammation, suggesting that adequate control of the inflammatory response can be accompanied by a marked improvement in hemodynamics in certain types of PH.     

Right ventricular aneurysm complicating right ventricular infarction

Right ventricular (RV) involvement commonly occurs in patients with acute inferior myocardial infarction and is associated with high mortality and morbidity. RV dysfunction and dilatation commonly recover in survivors; chronic RV dyskinesia and failure are rare complications. This case report presents a patient in whom an isolated RV aneurysm complicates a RV involvement of acute inferior-posterior myocardial infarction.     

Reversible left ventricular dyssynchrony and heart failure induced by right ventricular pacing

Right ventricular (RV) pacing related heart failure is reported in some patients after long term pacing. The exact mechanism is not yet clear but may be related to left ventricular (LV) dyssynchrony induced by RV apical pacing. We report one case with baseline normal LV ejection fraction but complicated by heart failure and ventricular tachycardia after 4 months of pacing for complete heart block together with illustration of LV dyssynchrony demonstrated by tissue Doppler imaging.     

Right Ventricular Function Evolution With Pregnancy in Repaired Tetralogy of Fallot

This case illustrates the evolution of right ventricular (RV) 3-dimensional (3D) area strain during pregnancy in a patient with repaired Tetralogy of Fallot. The report highlights impairment in RV function with pregnancy, suggesting the importance of prepregnancy RV systolic function assessment, especially using 3D echocardiography.     

High serum IgA and activated Th17 and Treg predict the efficacy of abatacept in patients with early,seropositive rheumatoid arthritis

Objective

To identify the predictive biomarkers for achieving remission with abatacept in patients with seropositive rheumatoid arthritis (RA).

Methods

We enrolled patients with RA who were treated with abatacept. We compared the baseline laboratory results and longitudinal immune-phenotyping data between patients who achieved remission and those who did not achieve remission at 6 months according to the clinical disease activity index.

Results

One hundred and twenty RA patients were enrolled. In the seropositive patients with early RA (n?=?24), high serum IgA levels, anti-citrullinated peptide (CCP) titers, and neutrophil counts before treatment were predictors of remission (area under the curve [AUC], 0.659, 0.741, and 0.704, respectively). Additionally, activated Th17 (aTh17) cells and activated Treg (aTreg) cells before treatment were found to be significantly higher in patients with remission compared to those without remission (2.9% vs 1.1%, P?=?0.02; 34.3% vs 17%, P?=?0.03, respectively). The measurement of longitudinal cell subpopulation revealed a decrease in the effector CD4 T cell population after abatacept treatment, which correlated with anti-CCP titers and neutrophil counts, and was associated with remission achievement. In seropositive patients with established RA (n?=?79), high RF titers and low IFN-γ levels were associated with the good response to abatacept.

Conclusion

Our study has shown that serum IgA levels, anti-CCP titer, and neutrophil counts are predictive biomarkers for predicting the response to abatacept in patients with seropositive and early RA and may reflect the inhibition of effector CD4 T cell subpopulations by abatacept.

Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment

OBJECTIVE: To examine the impact of added abatacept treatment on health related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX). METHODS: The impact of abatacept treatment on HRQoL was examined in a longitudinal, randomised double blind, placebo controlled clinical trial. Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups. The relationship between American College of Rheumatology (ACR) clinical markers and disease duration with changes in HRQoL indicators was also examined. Finally, a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population. RESULTS: Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures, including physical function, fatigue, all eight domains of the SF-36, and the physical and mental component summaries (PCS and MCS). Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains. By day 169, all HRQoL measures were significantly better with abatacept than with placebo. HRQoL gains were associated with greater ACR clinical improvement, and the effects were consistent for patients with different disease duration. A significantly greater percentage of patients treated with abatacept reached normative levels of PCS, MCS, physical functioning, and fatigue compared with patients treated with MTX alone. CONCLUSION: Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA.     

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease‐modifying antirheumatic drugs: A one‐year randomized,placebo‐controlled study

Objective

To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving ≥1 traditional nonbiologic and/or biologic disease‐modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study.

Methods

This was a 1‐year, multicenter, randomized, double‐blind, placebo‐controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo.

Results

The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%).

Conclusion

Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician‐ and patient‐reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.

     

Intracavitary metastatic hepatocellular carcinoma of the right ventricle

We report a rare case of direct intracavitary metastasis of a hepatocellular carcinoma (HCC) to the right ventricle (RV) without intravascular involvement. A 65-year-old female, with a history of HCC and partial right hepatectomy, developed symptoms of congestive heart failure. Echocardiography revealed a large tumor in the RV with extension to the outflow tract. Palliative excision of the cardiac tumor under cardiopulmonary bypass and cardioplegic arrest was performed due to severe hemodynamic compromise. The final pathology report disclosed metastatic HCC. Tumor recurrence in the RV was noted 2 months later and the patient succumbed to the disease.     

Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life

OBJECTIVE: This study examined the effect of abatacept, a costimulation modulator, on the health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA). METHODS: Three hundred thirty-nine patients with RA on a background of methotrexate (MTX), who participated in a multicenter, double-blind, placebo-controlled trial, were randomized to abatacept 2 mg/kg, abatacept 10 mg/kg, or placebo. HRQOL was assessed at pretreatment, and at 3, 6, and 12 months posttreatment using the SF-36 Health Survey (SF-36). Changes in SF-36 scores from baseline to 12 months were compared across treatment and placebo groups to examine HRQOL benefits of abatacept. A link between American College of Rheumatology improvement and changes in SF-36 scores was established to demonstrate the association between HRQOL outcomes and clinical response. RESULTS: After 12 months of treatment, patients randomized to abatacept 10 mg/kg showed significantly better HRQOL outcomes overall versus patients randomized to placebo (MANOVA F = 4.71, p < 0.001) or to abatacept 2 mg/kg (MANOVA F = 1.97, p = 0.05). Differences in SF-36 change scores between abatacept 10 mg/kg and placebo groups reached statistical significance on all 8 domain scales, the 2 summary measures, and the SF-36 utility index (SF-6D). Differences in SF-36 change scores between abatacept 10 mg/kg and abatacept 2 mg/kg reached statistical significance on 5 of the 8 domain scales, the physical summary measure, and the SF-6D. Improvement in HRQOL was highly related to clinical response. CONCLUSION Abatacept 10 mg/kg plus MTX demonstrated a stronger HRQOL response than placebo plus MTX. The abatacept 2 mg/kg arm showed a very weak and transient response.     

Silent inferior myocardial infarction with extensive right ventricular scarring

Right ventricular infarction (RVI) occurs in approximately 50% of patients with inferior myocardial infarction (MI). The assessment of RVI is important for identifying patients being at increased risk of in hospital mortality and poorer prognosis if impaired right ventricular (RV) systolic function is present. We report the case of an asymptomatic 38-year-old male who sustained a silent inferior myocardial infarction with extensive RV involvement. There was no history of myocardial ischemia and cardiovascular risk factors. Therefore, first cardiac magnetic resonance (CMR) imaging using delayed enhancement (DE) was performed and revealed a transmural inferior wall myocardial infarction of LV with extensive involvement of RV. This case illustrates the difficulties of conventional imaging modalities and invasive coronary angiography to depict an inferior myocardial infarction with RV involvement.     

Endomiocardite de Löffler – a propósito de um caso clínico

Loeffler's endocarditis is an acute form of primary restrictive cardiomyopathy. We report the case of a young woman with pleuritic chest pain associated with fever and hypereosinophilia. She was hospitalized with suspected acute myopericarditis and was treated with aspirin, leading to clinical improvement. Ten days after discharge, she was rehospitalized due to recurrence of chest pain. The echocardiogram showed what appeared to be a mass filling the apex of the right ventricle (RV). She was referred for magnetic resonance imaging, which revealed marked myocardial thickening in the apex of the RV. The patient underwent an endomyocardial biopsy, resulting in a diagnosis of eosinophilic endocarditis. After treatment with prednisolone, all symptoms and the eosinophilia disappeared, and there was complete remission of the RV abnormalities. After three years of follow-up, the patient remains asymptomatic. This case shows that, even without an etiologic diagnosis of eosinophilia, the prognosis for Loeffler's endocarditis can be favorable if treatment is initiated early.     

Head‐to‐head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: Findings of a phase IIIb,multinational, prospective,randomized study

Objective

There is a need for comparative studies to provide evidence‐based treatment guidance for biologic agents in rheumatoid arthritis (RA). Therefore, this study was undertaken as the first head‐to‐head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA.

Methods

Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2‐year study. The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year.

Results

Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval −5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept–treated patients and 88.6% for SC adalimumab–treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P = 0.006).

Conclusion

The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.