In the 2002 update of the American College of Rheumatology Guidelines for the Management of Rheumatoid Arthritis (1), the authors stress the need for antiplatelet therapy with low-dose aspirin for patients at risk for cardiovascular disease who are taking selective cyclooxygenase-2 (COX-2) agents, reasoning that, unlike nonselective nonsteroidal antiinflammatory drugs (NSAIDs), the selective COX-2 inhibitors have no effect on platelet adhesion or aggregation. This seems to imply that antiplatelet therapy with aspirin is required only when selective COX-2 inhibitors are used. I believe nonselective NSAIDs neither ensure appropriate antiplatelet prophylaxis, nor do they appear better than selective COX-2 inhibitors for patients at cardiovascular risk who are receiving concomitant aspirin antiplatelet therapy. Unlike the potent and irreversible inhibition of platelet COX-1 induced by aspirin, the antiplatelet effect of NSAIDs is highly variable and depends on two factors: their potency for inhibiting COX-1 at pharmacologic doses and their half-life (2). Thus, neither NSAIDs with a short half-life, such as ibuprofen, nor those with a relatively low COX-1 inhibitory effect, such as diclofenac, provide efficient and sustained antiplatelet therapy. Only drugs with a long half-life and a potent COX-1 inhibitory effect, such as indobufen, flurbiprofen, and naproxen, have been suggested to be potentially useful as antiplatelet agents (2). This may explain the observation of a higher rate of thrombotic events with rofecoxib than with naproxen in a large trial (3), something not observed when rofecoxib or celecoxib is compared with other nonselective NSAIDs (4,5). However, due to the reversibility of the antiplatelet effect of NSAIDs, the cardioprotective effect of these drugs as shown in clinical trials, where compliance with the dose and treatment schedule is usually better, does not necessarily apply to clinical practice, where intermittent use by patients is common. Accordingly, epidemiologic studies have failed to demonstrate cardioprotective effects of NSAIDs, in contrast with aspirin (6). Furthermore, recently published data demonstrate that in patients taking aspirin, ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin, whereas other drugs with lower COX-1 inhibitory effects, such as diclofenac or rofecoxib, do not interfere with aspirin's effects (7). An additional matter of concern when using aspirin with NSAIDs is their synergistic action in terms of gastrointestinal toxicity, something that has not been sufficiently evaluated for COX-2 selective drugs (8). In conclusion, neither relying on the antiplatelet effect of NSAIDs in patients at cardiovascular risk, nor using NSAIDs instead of selective COX-2 inhibitors when low-dose aspirin is needed, can be recommended based on available evidence.
The career of Medicine at the Pontificia Universidad Católica de Chile was established from the beginning (1929), with a classical Flexner curriculum design. In seven years, the career is divided in three cycles: basic sciences, clinics and internship. It obtained Chilean accreditation and fulfilled American Association of Medical Colleges accreditation requirements. Changes in the Chilean epidemiological profile and health system, and new teaching methods in medicine, stimulated a process of deep curricular analysis, identifying strengths and weaknesses of the medical career. The curricular strengths were well-developed scientific and clinical components, fully committed students and faculties, well defined learning objectives and excellent clinical campuses. Curricular weaknesses included a poor vertical and horizontal integration, few student centered methodologies and a weak emphasis concerning doctors professionalism. Subsequently, the whole community of teachers, students and medical educators worked on the design of a new curriculum, establishing a new graduate profile and designed it oriented by learning objectives, of six years of duration, with an optimized course sequence that melds basic science and clinical concepts, with strong emphasis on humanities and professionalism. It prioritizes an early contact with patients from the first year and expands teaching methods. The main objective of this process was to achieve a new curriculum with an integrative structure. This was implemented in 2015 with an approved protocol to evaluate the outcomes.
ANCA-associated vasculitides (AAV) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality. This group includes granulomatosis with polyangiitis (Wegener´s, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs. These have broad mechanisms of action as well as important adverse effects. Efforts have been made to investigate novel agents with better-defined and narrower mechanisms of action, such as biologics, including TNF-α blockers. Etanercept, a well-known TNF-α blocker evaluated for GPA in the Wegener's Granulomatosis Etanercept Trial (WGET), was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period. A 5-year follow-up after the WGET trial showed a sustained increase in incidence of solid malignancies, but this could no longer be solely attributed to etanercept exposure. These studies raised concerns about the use of the family of TNF-α blockers in AAV. Here, we review the evidence about the association between therapeutic inhibition of tumor necrosis factor (TNF-α) by etanercept and other TNF-α blockers with the development of solid malignancies in GPA and other AAV.
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