Interleukin-6 (IL-6) is a pivotal cytokine of innate immunity which enacts a broad set of physiologic functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome to interleukin-1 to IL-6 and on to the hepatically derived clinical biomarker C-reactive protein, an expanding literature has led to understanding of the pro-atherogenic role for IL-6 in cardiovascular disease and thus the potential for interleukin-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacologic inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiologic data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and anti-thrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of C-reactive protein, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.
Central nervous system (CNS) histoplasmosis is a rare manifestation of disease, often misdiagnosed due to the wide spectrum of neurological presentation. We present a rare case of CNS histoplasmosis in a 62-year-old male with untreated myeloproliferative disease who presented with altered mental status. This case emphasizes the clinical presentation and diagnostic difficulty in a patient with CNS histoplasmosis. We also highlight the importance of implementing a multidisciplinary approach in the medical management of disseminated histoplasmosis with CNS involvement.
Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.
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