Comparison of drug retention rates and causes of drug discontinuation between anti–tumor necrosis factor agents in rheumatoid arthritis

Objective

Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti‐TNF discontinuation in a population‐based RA cohort.

Methods

All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders.

Results

A total of 2,364 anti‐TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti‐TNF therapy was 37 months, but discontinuation rates differed between the 3 anti‐TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01–1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003–1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23–3.62). Other discontinuation causes were equally distributed between the anti‐TNF agents.

Conclusion

In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.     

The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study

OBJECTIVE: To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population-based cohort. The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone. METHODS: We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders. RESULTS: A total of 372 patients treated with anti-tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination-treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti-TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045). CONCLUSION: When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone.     

Systemic rheumatoid vasculitis: a review

OBJECTIVES: To review the most recent information on the incidence, clinical course, pathology, pathogenesis, diagnosis, and treatment of rheumatoid vasculitis (RV), including the still scanty data on the use of biologics. METHODS: PubMed and MEDLINE databases (1950-2006) were searched for the key words "vasculitis" and "rheumatoid arthritis"; and "rheumatoid arthritis" and "extra-articular manifestations." All relevant articles in English and French were reviewed. Additional words used in follow-up research include "anti-TNF," "rituximab," "IL-1 receptor antagonists," and "CTLA-4 Ig," all in conjunction with "vasculitis." Pertinent secondary references were also retrieved. RESULTS: RV is an inflammatory condition of the small- and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA) (approximately 1 to approximately 5%). It has a vast array of clinical manifestations with a predilection for the skin (peripheral gangrene, deep cutaneous ulcers) and the peripheral nervous system (mononeuritis multiplex). Because of the lack of specific signs and symptoms, the diagnosis relies on the exclusion of other causes of similar lesions (diabetes, atherosclerosis, drug reactions, infection, neoplasias) and, ideally, on the histopathological demonstration of necrotizing vasculitis. Despite the availability of a host of promising new drugs for the treatment of RA, no clinical trials have tested their efficacy in RV; therefore, its management remains largely empirical. CONCLUSIONS: Although RV has apparently been decreasing over the last 2 decades, possibly as a consequence of the more energetic approach to the management of RA currently used, it remains an important complication of RA that needs to be promptly recognized and treated.     

Mice deficient in hepatocyte-specific IL-1Ra show delayed resolution of concanavalin A-induced hepatitis

Interleukin-1 receptor antagonist (IL-1Ra) is a specific IL-1 inhibitor that possesses anti-inflammatory activities. Several studies in human and mouse suggested a protective role for IL-1Ra in liver inflammation, and we previously demonstrated that hepatocytes produce high levels of IL-1Ra in response to inflammatory challenge in vitro and in vivo. In the present study, we investigated the production and the biological function of hepatocyte-derived IL-1Ra in concanavalin A (ConA)-induced hepatitis in mice. We show that the injured liver produces large amounts of IL-1Ra and that secreted and intracellular IL-1Ra isoforms are produced with different kinetics during the course of hepatitis. By using hepatocyte-specific IL-1Ra-deficient mice (IL-1Ra(ΔH)), we demonstrate that hepatocytes represent the major cellular source of local IL-1Ra. Most interestingly, hepatic necrosis and inflammation were increased in IL-1Ra(ΔH) as compared with wild-type mice during the late phase of the disease, leading to a delayed resolution of hepatitis in IL-1Ra(ΔH) mice. In conclusion, our results show that the local production of IL-1Ra by hepatocytes contributes to the resolution of hepatitis.     

The influence of air pollution on cardiovascular and pulmonary function and exercise capacity: Canadian Health Measures Survey (CHMS)

Background

Air pollution has been associated with adverse cardiovascular effects.

Objective

To measure the association between air pollution, spirometry, blood pressure, and exercise capacity.

Methods

We used data from 5604 subjects collected during the Canada Health Measures Survey to test the association between air pollution measured on the day of the survey and spirometry (n=5011 subjects), blood pressure, and exercise capacity (n=3789 subjects).

Results

An interquartile range (IQR) increase in ozone (17.0 ppb) was significantly associated with a 0.883% higher resting heart rate, a 0.718% higher systolic and 0.407% higher diastolic blood pressure, a 0.393% lower FEV₁/FVC expressed as a percentage of predicted, and a 1.52% reduction in the aerobic fitness score (p<0.05). Resting systolic and diastolic blood pressure were approximately 0.5 mmHg higher for an (IQR 4.5 μg/m³) increase in PM_2.5 (IQR 4.5 μg/m³) and 1 mmHg higher for a 12.6 ppb increase in NO₂ (IQR 12.6 ppb). An increase in PM_2.5 was also associated with an approximate 0.4% decrease in percent predicted FEV₁ and FVC (p<0.05).

Conclusion

Exposure to higher concentrations of air pollution was associated with higher resting blood pressure and lower ventilatory function. Ozone was associated with reduced exercise capacity.     

The links of hepcidin and erythropoietin in the interplay of inflammation and iron deficiency in a large observational study of rheumatoid arthritis

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.     

Foraging optimally in social neuroscience: computations and methodological considerations

Research in social neuroscience has increasingly begun to use the tools of computational neuroscience to better understand behaviour. Such approaches have proven fruitful for probing underlying neural mechanisms. However, little attention has been paid to how the structure of experimental tasks relates to real-world decisions, and the problems that brains have evolved to solve. To go significantly beyond current understanding, we must begin to use paradigms and mathematical models from behavioural ecology, which offer insights into the decisions animals must make successfully in order to survive. One highly influential theory—marginal value theorem (MVT)—precisely characterises and provides an optimal solution to a vital foraging decision that most species must make: the patch-leaving problem. Animals must decide when to leave collecting rewards in a current patch (location) and travel somewhere else. We propose that many questions posed in social neuroscience can be approached as patch-leaving problems. A richer understanding of the neural mechanisms underlying social behaviour will be obtained by using MVT. In this ‘tools of the trade’ article, we outline the patch-leaving problem, the computations of MVT and discuss the application to social neuroscience. Furthermore, we consider the practical challenges and offer solutions for designing paradigms probing patch leaving, both behaviourally and when using neuroimaging techniques.     

Case of metastatic glioblastoma with primitive neuronal component to the lung

Glioblastoma (GBM) with primitive neuronal component (GBM‐PNC) is a rare GBM subtype recently categorized by the World Health Organization in the revised classification system of 2016. Extracranial metastases originating from GBM‐PNC are rare and metastasis to solid organs has never been reported. Herein, we present the first case of metastasis of GBM‐PNC to the lung. A 49‐year‐old man presenting with headache was diagnosed with multiple tumors adhering to the dura matter in the right temporal lobe. Despite surgery and chemoradiotherapy, 2 months after the initial therapy, the patient presented with CSF dissemination and lung metastases. The patient succumbed to the disease 12 months after the first surgery. We discuss the possibility that GBM‐PNC may constitute a subtype of glioma with particularly poor prognosis, tending to dissemination and metastasis. Our results suggest that a complementary regular inspection of the whole body via CT may be recommended for the follow‐up of patients with GBM‐ PNC.     

Assessment of the efficacy of different statins in murine collagen‐induced arthritis

Objective

Hydroxymethylglutaryl‐coenzyme A reductase inhibitors (statins) are widely used lipid‐lowering agents. In addition to their well‐known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen‐induced arthritis, a well‐described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model.

Methods

Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols.

Results

Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti–type II collagen IgG production), and biochemical (interleukin‐6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels.

Conclusion

This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune‐mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.