By Santosh Vardhana
Faculty Peer Reviewed
After the greatest professional sporting day of the year, count on Primecuts to bring football and medical science together without the requisite discussion of dementia pugilistica! As all-time great Packers’ coach Vince Lombardi said, “The best defense is a great offense.” Numerous articles in the past few weeks may help arm physicians with better offensive weapons for the attack against inflammation, infectious disease, and cardiovascular disease.
New strategies have been few and far between with respect to lupus, for which no drug has been FDA approved in over thirty years. Recent excitement has surrounded targeting B lymphocyte stimulator (BlyS), a co-stimulatory molecule that is critical for B cell survival and is overexpressed in patients with SLE. Prior results of a phase 2 placebo controlled trial suggested a significant benefit of belimumab, an anti-BlyS human monoclonal antibody, in a large proportion of patients with highly seropositive lupus (high titers of ANA or anti-dsDNA) [1]. This week, Lancet published results of a phase 3 trial of 867 adult patients with highly active disease and high ANA or anti-dsDNA titers randomized to either belimumab or placebo, which demonstrated a nearly twofold likelihood of significant improvement using a highly validated SLE activity index [2]. This improvement was particularly strong in eastern European patients, who had a fivefold increased likelihood of improvement. Additionally, patients were significantly less likely to experience a lupus flare in the first year following treatment, were more likely to be able to reduce their standing dose of prednisone, and showed significant improvements in hypocomplementemia, hypergammaglobulinemia, and anti-dsDNA titers. Notably, this study excluded pregnant patients, patients with renal or CNS disease, and patients with any history of anti-B cell treatment. It is also important to note that while both subjective and objective measures of improvement were reported, mortality was not measured as either a primary or secondary endpoint; this will be of significant interest in future studies.
We stay in the realm of near-to-market phase 3 trials but move from autoimmune to iatrogenic disease. Clostridium difficile colitis remains a potent problem, both in hospitals where it occurs after broad-spectrum antibiotic therapy and now in the community, where the particularly virulent NAP1 strain causes colitis without prior antibiotics [3]. Fidaxomicin, a new antibiotic to combat Clostridium difficile, has minimal systemic absorption, achieves high fecal concentrations, and causes limited toxicity against endogenous gut flora. Results of a phase 3 prospective randomized control trial of patients with either the first or second episode of Clostridium difficile colitis published in the New England Journal of Medicine suggest that rates of recurrence were reduced by treatment with the oral fidaxomicin as compared to oral vancomycin [4]. However, it should be noted that this study excluded patients with fulminant infection or more than one recurrent episode; furthermore, fidaxomicin was not more effective among patients with the highly virulent NAP1 strain seen with more prevalence in the community, thus diminishing its benefits in the area where new therapies are most needed.
In the showdown against cardiovascular disease, statins have been the MVPs of a physician’s arsenal. Originally thought to reduce cardiovascular risk by acting as lipid-lowering agents, statins have been shown to have additional anti-inflammatory properties [5]. The JUPITER trial took this idea a step further by suggesting that patients with low LDL (<130 mg/dL) but elevated CRP (> 2 mg/L) have a cardiovascular benefit from statin therapy that extends beyond the anti-lipid effect, thus calling into question the proper indications for statin therapy [6]. In fact, a recent paper suggested that LDL goals might not be the only targets for statin therapy [7]. This debate will only be amplified by a recent study published in Lancet, which analyzed results of the Heart Protection Study, which randomized 20,536 patients at high risk of vascular events (CAD, non-coronary occlusive vascular disease, diabetes mellitus, or men > 65 receiving treatment for HTN) to receive simvastatin or placebo between 1994 and 1997. Overall, simvastatin reduced major vascular events over 5 years by 24% in a manner that was notably independent of CRP concentration and occurred even in patients with baseline CRP < 1.25 [8]. In fact, the proportional reduction in rate of vascular events was similar between patients with low LDL and low CRP to patients with high LDL and high CRP, further supporting the theory that statins’ pleotropic effects confer great risk reduction independent of LDL and CRP. A critical concern is that this study did not distinguish between statins as primary or secondary prevention (greater than 40% of patients enrolled in the study had previously had an MI), but nevertheless, it suggests that all patients with cardiovascular risk should consider a statin regardless of LDL or CRP levels.
We move from the bedside to the bench as we look for emerging therapies in the management of cardiovascular disease. Ischemic cardiomyopathy is an emerging chronic problem, particularly as survival from myocardial infarctions continues to increase. A study published this week in Circulation focuses on the therapeutic potential for the growth hormone Fibroblast Growth Factor 9 (FGF9). FGF9 is an important growth factor during mid-gestational heart development, when it is released from epicardial myocytes stimulating an outside-in gradient for coronary artery formation and cardiac hypertrophy in the developing heart, but it is not expressed in adult tissues and not upregulated following an MI. In this study, mice with conditional myocardial expression of FGF9, which was stimulated following MI induction via coronary artery ligation, demonstrated microvessel expansion, reduced interstitial fibrosis, improved systolic function, and reduced heart failure mortality [9]. While gene therapy remains relatively far on the horizon, studies such as this maintain hope for reversing the course of such heart disease.
Another laboratory-driven discovery suggests the possibility of reversal of neurological disease following spinal cord injury. A study published this week in Science started with the recent discovery that the extracellular matrix deposition that prevents neuronal recovery following spinal cord injury appears highly dependent on dynamic microtubule activity [10]. The authors found that intrathecal administration of paclitaxel (Taxol), a microtubule stabilizing drug, significantly reduced extracellular matrix deposition and permitted increased regenerative fiber growth after dorsal spinal cord hemisection, thus presumably effecting significant functional recovery as measured by accurate paw placement on a gridwalk test [11]. This novel use of a chemotherapeutic drug may markedly alter the prognosis of patients who suffer devastating spinal cord injuries.
From the neurologic to the cerebrovascular, another area in which physicians suffer from a lack of effective therapeutic options is stroke, for which only rapid administration of thrombolytic agents and early physical rehabilitation have been shown to improve motor function. After the publication of a small case series that demonstrated motor cortex hyperactivation in healthy as well as post-stroke individuals, a study in The Lancet Neurology randomized 118 patients with a recent stroke and subsequent motor dysfunction to fluoxetine or placebo [12]. At 90 days, fluoxetine significantly improved motor function, ability to independently perform ADLs, and incidence of depression (7% versus 29%). The study was limited by exclusion of patients with prior strokes or other comorbidities that precluded proper assessment of motor function, but it still offers new hope in an area where treatment options are few.
Of course, like a quarterback who throws a devastating interception for every spectacular touchdown pass, so often do physician’s strongest therapies act as double-edged swords. This week’s JAMA highlights this fact in the area of cancer chemotherapy, where the treatment can often be as damaging as the disease. Bevacizumab (Avastin) is a monoclonal antibody that blocks VEGF-induced angiogenesis in tumors, and it was rapidly approved as part of combination therapy for colorectal cancer, NSCLC, breast cancer, renal cell carcinoma, and glioblastoma multiforme. However, serious adverse events related to its vascular effects have been reported, and a meta-analysis this week demonstrated an increased risk of fatal adverse events in patients treated with bevacizumab, particularly in patients receiving concurrent platinum or taxane-based chemotherapy [13].
Thus, in the past week, new studies provide physicians with an variety of strategies for putting points on the board against cardiovascular, neurologic, autoimmune, and infectious disease, while offering caution regarding a widely used chemotherapeutic agent. On the other hand, in the spirit of Super Bowl Sunday, we shouldn’t forget legendary football coach Paul “Bear” Bryant’s saying, “Offense sells tickets; defense wins championships.” In medicine, it is often said that prevention is the most effective cure. This may be particularly true in the case of cerebrovascular events, in which prophylactic anticoagulation in patients with atrial fibrillation and high risk of embolic events as determined by the CHADS(2) criteria has been shown to reduce the incidence of thromboembolic events. The primary pitfall of this strategy, however, has been the difficulty in treating patients with an intermediate risk of stroke (CHADS(2) = 1). This week, an article in the British Medical Journal described a new scale, CHA(2)DS(2)-VASc, which adds vascular disease, age 65-74, and female sex to the risk stratification. CHA(2)DS(2)-VASc was shown to be more effective at stratifying low risk versus high risk patients as compared to CHADS(2) criteria [14]. Given the significant complications associated with warfarin, adopting this scale may more effectively identify patients for whom anticoagulation is worth the risk.
Prevention also often takes the form of either prophylactic medication or vaccination. A study published in the New England Journal of Medicine this week offers a new defense against HPV-induced anogenital condyloma and anal, penile, and oropharyngeal squamous cell carcinoma in males. Vaccination with the quadrivalent HPV vaccine, which is nearly 100% effective in preventing HPV-induced cervical cancer [15], induced an antibody response in nearly 100% of men between 16 and 26 within 1 month and reduced incidence of HPV-induced SCC 60.2%, and 83.8% in patients who successfully completed all three rounds of vaccination [16]. It is unclear why this vaccine was less effective in men than women and why efficacy was significantly worse in men who have sex with men; this is of particular concern considering that the study excluded patients with more than five lifetime sexual partners and therefore may underestimate the exposure of patients likely to receive the vaccine.
So often, the key to an effective defense is accurate scouting; this week, a variety of studies describe new advances in information gathering in both infectious and neoplastic disease. First, an internally controlled prospective trial in Annals of Internal Medicine showed that mandatory usage of sterile gloves by phlebotomists reduced blood culture contamination rates by 50%. While this only amounted to an absolute risk reduction for specimen contamination of 0.4% in this study, mandatory use of sterile gloves may be beneficial in inpatient settings with a high risk of fulminant infection [17]. Second, a urine test that screens for the presence of a c-polysaccharide antigen relatively specific to pneumococci was able to detect evidence of pneumococcal infection in up to fifteen percent of patients hospitalized for community acquired pneumonia when no other etiology was found (although it should be noted that the test was far less sensitive than conventional sputum analysis) [18]. Third, a new study in The Lancet addressed the growing need for a screening test for variant Creutzfeldt-Jakob disease, whose elevated asymptomatic carrier rate (up to 200 per million people) and demonstrated transmission through blood transfusions makes it a concerning public health risk. Effective blood-based testing has been difficult because the responsible agent is an endogenous protein PrP, which becomes an insoluble, spontaneously aggregating form (PrPsc) in symptomatic prion disease, but is otherwise natively expressed at high levels in the CNS and blood. This study, however, took advantage of the selective propensity of misfolded PrP to bind metals (which is why it is often found on medical hardware) in order to enrich the pathogenic form of this endogenous peptide. By this method, the test was able to identify symptomatic vCJD patients with 71.4% sensitivity and 100% specificity [19]. While this is orders of magnitude better than any previous serum assay for vCJD, its relatively low sensitivity, even in symptomatic patients, highlights the need for future investigations into better testing for asymptomatic vCJD carriers.
Finally (and most delightfully), a new study published in Gut shows that man’s best friend may be even better than previously thought. In this study, labrador retrievers trained specifically in cancer scent detection were able to identify colorectal cancer with 91% sensitivity and 99% specificity in breath samples, and 97% sensitivity and 99% specificity in stool samples [20]. Even more fascinating, the dogs’ ability to identify cancer was not confounded by smoking, benign colorectal disease, or inflammatory bowel disease. While routine employment of dogs for cancer screening is likely not cost-effective, the presence of cancer-specific volatile organic compounds may allow for effective non-invasive testing in the future.
Tune in for the next Primecuts on Clinical Correlations, where we don’t know the meaning of “off-season.”
Dr. Vardhana is a 4th year MD/PhD student at NYU Langone Medical Center
Peer reviewed by Barbara Porter, section editor, Clinical Correlations
References:
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