The prevalence of use of long-term systemic glucocorticoid therapy in the general adult population is 1 %. This figure increases to up to 3 % in elderly women. Metabolic (i.e. diabetes mellitus, ...dyslipidemia, weight gain, lipodystrophy) and cardiovascular (i.e. hypertension, cardiovascular events) adverse events are commonly observed in these patients and can be life threatening. Paradoxically, there is very few data on some of these adverse events and many of the available studies remain inconclusive. Incidence of and risk factors for dyslipidemia, weight gain and lipodystrophy are poorly defined. The optimal treatment plan for patients diagnosed with glucocorticoid-induced diabetes or hypertension is undetermined. Finally, there is no medical consensus on the best strategies for the prevention and detection of these complications. However, certain of these questions can be answered by looking at available data on patients with endogenous hypercortisolism (i.e. Cushing's syndrome). This article reviews the pathophysiology, incidence, risk factors, screening, and treatment of glucocorticoid-induced weight gain, lipodystrophy, diabetes, dyslipidemia, hypertension, and cardiovascular events. It also focuses on the possible prevention of these adverse events by targeting the glucocorticoid receptor using selective glucocorticoid receptor modulators.
Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact ...of glucocorticoid exposure duration and predisposing factors on this risk.
The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 interquartile range 48-73 y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15-30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83-2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61-6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential confounders would have radically changed the findings. Limitations of our study include the use of electronic medical records, which could have resulted in some degree of misclassification of the infectious outcomes; a possible reporting bias, as general practitioners could be more prone to record an infection in those exposed to glucocorticoids; and a low number of events for some outcomes such as scabies or varicella, which may have led to limited statistical power.
The relative risk of LRTI and local candidiasis is very high during the first weeks of glucocorticoid exposure. Further studies are needed to assess whether low albumin level is a risk factor for infection by itself (e.g., by being associated with a higher free glucocorticoid fraction) or whether it reflects other underlying causes of general debilitation.
Objective
Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or ...hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome.
Methods
A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n = 162), were judged by experts to not have reactive hemophagocytic syndrome (n = 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n = 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets.
Results
Nine variables (3 clinical i.e., known underlying immunosuppression, high temperature, organomegaly, 5 biologic i.e., triglyceride, ferritin, serum glutamic oxaloacetic transaminase, and fibrinogen levels, cytopenia, and 1 cytologic i.e., hemophagocytosis features on bone marrow aspirate) were retained in the HScore. The possible number of points assigned to each variable ranged from 0–18 for known underlying immunosuppression to 0–64 for triglyceride level. The median HScore was 230 (interquartile range IQR 203–257) for patients with a positive diagnosis of reactive hemophagocytic syndrome and 125 (IQR 91–150) for patients with a negative diagnosis. The probability of having hemophagocytic syndrome ranged from <1% with an HScore of ≤90 to >99% with an HScore of ≥250.
Conclusion
The HScore can be used to estimate an individual's risk of having reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/).
The incidence and the risk of suicidal behaviors and severe neuropsychiatric disorders in people treated with systemic glucocorticoids are poorly known. The authors assessed the incidence rates of ...depression, mania, delirium, panic disorder, and suicidal behaviors in patients treated with glucocorticoids in primary care settings and the risk factors for developing these outcomes.
Data were obtained for all adult patients registered between 1990 and 2008 at U.K. general practices contributing to The Health Improvement Network (THIN) primary care database. The incidence rates for the outcomes of interest were assessed in patients who received prescriptions for oral glucocorticoids and compared with those in patients who did not receive such prescriptions. The predictors of these outcomes in exposed patients were ascertained using Cox proportional hazards models.
Overall, 786,868 courses of oral glucocorticoids were prescribed for 372,696 patients. The authors identified 109 incident cases of suicide or suicide attempt and 10,220 incident cases of severe neuropsychiatric disorders in these patients. The incidence of any of these outcomes was 22.2 per 100 person-years at risk for first-course treatments. Compared to people with the same underlying medical disease who were not treated with glucocorticoids, the hazard ratio for suicide or suicide attempt in exposed patients was 6.89 (95% CI=4.52–10.50); for depression, 1.83 (95% CI=1.72–1.94); for mania, 4.35 (95% CI=3.67–5.16); for delirium, confusion, or disorientation, 5.14 (95% CI=4.54–5.82); and for panic disorder, 1.45 (95% CI=1.15–1.85). Older men were at higher risk of delirium/confusion/disorientation and mania, while younger patients were at higher risk of suicide or suicide attempt. Patients with a previous history of neuropsychiatric disorders and those treated with higher dosages of glucocorticoids were at greater risk of neuropsychiatric outcomes.
Glucocorticoids increase the risk of suicidal behavior and neuropsychiatric disorders. Educating patients and their families about these adverse events and increasing primary care physicians' awareness about their occurrence should facilitate early monitoring.
Abstract Objectives Current knowledge in reactive hemophagocytic syndrome mainly relies on single-center case series including a relatively small number of patients. We aimed to identify a ...multicenter large cohort of adult patients with reactive hemophagocytic syndrome and to describe relevant clinical and laboratory features, underlying conditions, and outcome. Methods We conducted a multicenter study in 3 tertiary care centers in France over a 6-year period. The medical files of 312 patients with suspected hemophagocytic syndrome were retrospectively reviewed. Patients were classified with a positive, negative, or undetermined diagnosis of hemophagocytic syndrome by experts' consensus. Results Among the 312 patients fulfilling our inclusion criteria, 162 were classified with positive hemophagocytic syndrome (male, 67%; median age, 48 35-62 years). Compared with patients without hemophagocytic syndrome, patients with hemophagocytic syndrome more frequently had an underlying immunodepression (45% vs 33%, P = .03) and exhibited higher temperature, ferritin, triglycerides, aspartate transaminase, bilirubin, lactate dehydrogenase, and C-reactive protein, and lower hemoglobin, leukocytes, platelets, and sodium levels. Only 70% of them had hemophagocytosis features on bone marrow aspiration. Hematologic malignancies, especially non-Hodgkin lymphomas, were the main trigger of hemophagocytic syndrome, accounting for 56% of cases. The early mortality rate (ie, within 1 month after diagnosis) was 20%. Patients with hematologic malignancies-associated hemophagocytic syndrome had a poorer early outcome than those with underlying infection. Conclusions In this large, multicenter study, hematologic malignancies are the main disease associated with hemophagocytic syndrome in adults. Early mortality is high, and outcome is influenced by the underlying disease.
ObjectivesTo study trends in use of oral glucocorticoids (GCs) among adults, characteristics of oral GC initiators and prescriptions for the prevention of potential adverse effects associated with GC ...therapy.DesignFirst, a cross-sectional study repeated yearly was performed from 2007 to 2014 in a nationwide representative sample. Second, characteristics of initiators and patterns of GC therapy during the year following treatment initiation were described in a cohort of patients who began GC between 2007 and 2013.SettingPopulation-based study using data from the French reimbursement healthcare system (covering approximately 90% of the population) in patients aged ≥18 years.ResultsOver the study period, the prevalence of oral GC use ranged from 14.7% to 17.1% (95% CI 17.0%–17.2%) with a significant increase of 14.1% (95% CI +13.5% to +14.8%). The 2007–2013 cohort of oral GC initiators comprised 206 759 individuals. Oral GC use was mostly short-term (68% of unique reimbursement) and more than half of short-term users took concurrent antibiotics or respiratory/otological drugs. Chronic users (≥6 reimbursements/year) represented 1.8% (n=3789) of the cohort. The proportion of chronic users with comorbidities likely to be worsened by GC use (diabetes, psychotic disorders, osteoporosis) was 25%. Among patients at increased risk of osteoporosis, 62% received specific prevention/monitoring measures and only 27% had a bisphosphonate. Half of chronic oral GC users had a concurrent reimbursement of a proton pump inhibitor in the absence of non-steroidal anti-inflammatory drug use.ConclusionsOral GC use was highly widespread and increased among adults from 2007 to 2014. The overwhelming short-term use could mainly concern a growing use of unjustified prescriptions rather than situations with a favourable benefit/risk ratio. For chronic users, our findings plead for the development of interventions designed to improve monitoring with regard to the frequent comorbidities at risk and inappropriate prescribing of preventive therapeutic measures.
The diagnosis of the reactive form of hemophagocytic syndrome in adults remains particularly difficult since none of the clinical or laboratory manifestations are specific. We undertook a study in ...order to elicit which features constitute helpful criteria for a positive diagnosis. In this Delphi study, the features investigated in the questionnaire and the experts invited to participate in the survey were issued from a bibliographic search. The questionnaire was iteratively proposed to experts via a web-based application with a feedback of the results observed at the preceding Delphi round. Experts were asked to label each investigated criterion in one of the following categories: absolutely required, important, of minor interest, or not assessable in the routine practice environment. A positive consensus was a priori defined as at least 75% answers observed in the categories absolutely required and important. The questionnaire investigated 26 criteria and 24 experts originating from 13 countries participated in the second and final Delphi round. A positive consensus was reached for the nine following criteria: unilineage cytopenia, bicytopenia, pancytopenia, presence of hemophagocytosis pictures on a bone marrow aspirate or on a tissue biopsy, high ferritin level, fever, organomegaly, presence of a predisposing underlying disease, and high level of lactate dehydrogenase. A negative consensus was reached for 13 criteria, and an absence of consensus was observed for 4 criteria. The study constitutes the first initiative to date for defining international guidelines devoted to the positive diagnosis of the reactive form of hemophagocytic syndrome.
Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe ...psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as ways to prevent and treat these disturbances. An illustrative case vignette is presented describing a patient's experience of cycles of manic-like behavior and depression while on high-dosage prednisone, with long-term cognitive disorganization, vulnerability to stress, and personality changes. Severe neuropsychiatric consequences (including suicide, suicide attempt, psychosis, mania, depression, panic disorder, and delirium, confusion, or disorientation) have been reported to occur in 15.7 per 100 person-years at risk for all glucocorticoid courses, and 22.2 per 100 person-years at risk for first courses. The majority of patients experience less severe but distressing and possibly persistent changes in mood, cognition, memory, or behavior during glucocorticoid treatment or withdrawal. Although prediction of such effects is difficult, risks vary with age, gender, dosage, prior psychiatric history, and several biological markers. Key mechanisms thought to underlie these risk factors are briefly described. Recommendations are given for identifying individual risk factors and for monitoring and managing adverse neuropsychiatric effects of glucocorticoids.
PDF
