Corticosteroids even short term increase adverse events

Corticosteroids, prescribed for as many as one in five Americans in commercial insurance plans, can significantly increase the risk for adverse effects even when given short term, as found in a study recently published in BMJ (British Medical Journal). The authors note that though the severe adverse effects of longer term use or oral corticosteroids is well known, little has been understood about short term risks.

“…long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome…Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events…In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians.”

Corticosteroids often used where evidence is lacking

Until now little is know about the potential harms of short term use for the range of outpatient conditions for which they are often prescribed.

“…anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.”

Thus they set out to correlate short term use in an outpatient population and the risk of acute adverse events by analyzing data for 1,548,945 subjects who were prescribed oral corticosteroids for less than 30 days (non-oral forms were excluded from this study).

“We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety.”

The most common prescription was a six day methylprednisolone “dosepak”, most commonly given for upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders by family medicine and general internal medicine practitioners, but also by specialists in emergency medicine, otolaryngology, and orthopedics.

Significantly higher rates of sepsis, venous thromboembolism, and fracture

The authors identified a serious risk:

“Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).”

It defies common sense to use an agent that suppresses the immune system during an infection in all but the rare cases of severe immune excess, especially when there are numerous, more benign alternatives.

Quoted in Medscape Family Medicine, lead author Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, states:

“On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. “If there are alternatives to steroids, we should be use those when possible,” he said in the release. “Steroids may work faster, but they aren’t as risk-free as you might think.”

From the study:

  • This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

  • Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

  • Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

The authors conclude:

“Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

Women’s heart risk lower with exercise 2-3x/week than daily

CirculationExercise is a measured stress applied to the body to exploit a desirable genetic, cardiometabolic, endocrine and immune response. Like almost every other physiological intervention there is a dose-response curve: too little doesn’t elicit a sufficient reaction while the benefits degrade and harm can accrue with too much (over-training). A large study using data from 1.1 million women recently published in the journal Circulation offers evidence that strenuous physical activity 2-3 times per week significantly lowered their coronary heart disease risk while more frequent strenuous exercise actually increased it. The authors state:

“Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease…We describe here the relationships of the frequency, duration, and type of physical activity with incident CHD, cerebrovascular disease (overall and separately for hemorrhagic and ischemic stroke), and VTE (venous thromboembolism, overall and separately for those with and without pulmonary embolism), excluding the first 4 years of follow-up from recruitment into the study to limit the possible effects of reverse causation attributable to preclinical disease.”

They note the findings of a previous study on cardiovascular mortality in both sexes and running frequency:

“A recent prospective study of men and women aged 44 years on average at baseline, suggested a U-shaped association between running frequency and cardiovascular mortality. Although the lowest risk appeared to be among those reporting running 3 times per week, the confidence intervals were large.”

The low central portion of the ‘U’ corresponds to decreased mortality with exercise of moderate frequency.

Less cardiovascular disease with strenuous exercise 2-3 times per week

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

The authors analyzed data on physical activity an exercise for 1.1 million women without prior vascular disease along with and many other personal characteristics in including time spent walking, cycling, gardening, and housework each week. This was linked to National Health Service (UK) cause-specific hospital admissions and death records. The adjusted relative risks were calculated for first vascular events in relation to physical activity:

“During an average of 9 years follow-up, 49 113 women had a first coronary heart disease event, 17 822 had a first cerebrovascular event, and 14 550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions. However, women reporting strenuous physical activity daily had higher risks of coronary heart disease, cerebrovascular disease, and venous thromboembolic eventsthan those reporting doing such activity 2 to 3 times per week.”

They comment on these results:

“Results from this prospective study of 1.1 million UK women showed that women who engaged in physical activity had a lower incidence of CHD, cerebrovascular disease, and VTE than women who were inactive. Overall, the main difference in risk was between those doing some activity versus none, with the lowest risks being observed among women doing moderate amounts of activity. These associations were evident for different pathological types of stroke and of VTE, and across analyses using different measures of physical activity, including the frequency of any or strenuous activity, excess MET-hours expended, and durations of specific types of activity. Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and some evidence of an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group, compared to those who were moderately active.”

Keep up the moderate exercise, no need to push harder

The data suggests that pushing past moderation goes over the hump of the dose-response curve into over-training with degraded outcomes. The authors conclude:

“Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity.”

Strenuous endurance exercise promotes inflammation

PLOS ONEChronic inflammation, the common denominator of aging and most chronic diseases, is promoted by an imbalance between proinflammatory Th17 cells that drive autoimmunity and the anti-inflammatory Treg cells (regulatory T cells). An important study published in PLOS One reveals one of the mechanisms by which more than moderate strenuous exercise can increase cardiovascular risk. The authors state:

“Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes.”

Crucial Th17/Treg balance

There is a wealth of scientific evidence for the importance of the Th17 and Treg interplay in autoimmunity and chronic inflammation. The authors of this study note:

T helper (h)17 cells are CD4+ lymphocytes that produce Interleukin (IL)-17, a cytokine that play a crucial role in allergic inflammation and are known as powerful pro-inflammatory cells that promote autoimmunity. On the other end of the spectrum CD4+CD25+ regulatory T cells (Tregs) are differentiated T lymphocytes actively involved in control of peripheral immunity. The identification of these cells has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes.”

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

They examined the effect of strenuous exercise on the balance between pro-inflammatory effector and anti-inflammatory regulatory CD4+ lymphocytes in the blood of trained athletes who performed in the Emek-Hayarden Half Ironman triathlon or the 2009 Tiberia marathon and documented a marked pro-inflammatory shift:

Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls’ decreased in vitro after incubation with athletes’ post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies.”

Bottom line

Patients at risk for ‘sedentary death syndrome’ should be enthusiastically encouraged to have a dose of HIIT exercise 2-3 times per week, a fundamental life-style factor that reduces risk across the whole spectrum of chronic disease. HIIT (high intensity interval training) in particular efficiently yields desired cardiometabolic and other benefits with reduced risk for injury. The authors conclude:

“Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.”