The conduct of this survey was similar to previous cross-sectional surveys with participants recruited via patient organizations [5
]. The current survey of 1245 respondents is to our knowledge the largest patient survey to date in patients with AI. Previous studies have shown that outcomes in patients with AI are compromised [12
]. The responses from this survey provide more information on the impact of the disease and its treatment on patient-perceived outcomes, and support previous data showing a large impact of the disease and its treatment on the daily life of these patients.
Therapy traditions differ to some extent between countries but hydrocortisone was the most commonly used therapy in this survey (75%), irrespectively of country, which is also in line with previous studies from Europe [4
]. The distribution of therapies, i.e. type of glucocorticoid, was similar between patients with primary and secondary AI. Three quarters of the patients were on a BID or TID regimen. One unexpected observation in this survey was the high percentage (58%) of patients on prednisone/prednisolone who were on a BID or TID regimen.
That multiple daily dosing is a problem from a compliance point of view is well known from other therapies [21
]. The free-text answers to the open questions of this survey confirmed that multiple daily dosing is not optimal in AI and has an impact on patients’ social life and work life. More specifically, 4 of 10 patients in this survey found multiple daily dosing to be a problem. The impact on leading a normal life was attributed both to multiple dosing and to fluctuations in mental/physical energy over the day as multiple daily dosing with hydrocortisone/cortisone acetate causes peaks and low trough values in-between dosing occasions. When asked about the most important features of an optimal replacement medication, the patients ranked efficacy over 24 hours first and few side effects second. More patients on TID were satisfied with their treatment compared to those on BID or OD treatment. This might be attributable to the better cortisol coverage of TID during the active part of the day [22
] over the convenience of fewer dosing times.
The results from this survey are in line with a recently published clinical study [24
] which showed that a majority of the patients preferred the four-daily dosing regimen to twice daily when comparing equal doses of hydrocortisone given either twice daily or four times daily. The reasons reported were less fatigue, more alertness during the day, less headache and a feeling that the treatment effect was less varying during the day. The patients had complaints after the study that a four-dose regimen may be difficult to manage in the long run [24
]. Another study has shown that a thrice-daily administration with weight-adjusted doses provides a better PK profile within the constraints of immediate-release hydrocortisone formulations [25
]. 85% of the patients opted to remain on the TID regimen given in that study. These data suggest that patients experience benefits of having increased cortisol coverage during the active part of the day. One caveat of the above studies is that the total exposure of cortisol is higher when the same daily dose of hydrocortisone is administered divided into three or four daily doses than at BID administration. This is due to the fact that increasing the dose of hydrocortisone at one dose occasion does not result in a proportional increase in total exposure of cortisol due to the non-linear bioavailability of orally administered hydrocortisone [26
]. Thus, there might be a short-term perceived benefit of the increased cortisol exposure whereas the long-term risk may increase.
It is difficult to mimic physiological cortisol profiles with immediate release hydrocortisone replacement therapies [22
]. Therefore, attempts to better mimic the normal cortisol profiles have been made by developing new treatment regimens using the concept of chronotherapy, i.e. considering circadian rhythms in determining the timing and amount of the medication to optimize the desired effects and minimize the undesired ones [17
]. A once-daily treatment with dual action, combining immediate release and extended release hydrocortisone has shown benefit over immediate release hydrocortisone with the same daily dosing administered thrice daily in patients with adrenal insufficiency [28
Two thirds of the participants reported impacted QoL from their illness. In line with this being a patient survey (capturing the patient’s general perception of their subjective health at only one time point) and not a clinical trial, the questionnaire used in this survey did not include validated QoL questions from specific QoL questionnaires. Instead, the included questions were focused on the patients’ general perception of how and to what degree their disease and/or treatment affected their QoL. This survey showed that patients with secondary AI perceived their QoL as more impaired than patients with primary AI, which is in agreement with a previous study using validated QoL questionnaires showing that patients with AI have compromised QoL and that the impairment of QoL is worse in patients with secondary AI [14
]. The current survey did not collect data on co-morbidities. Patients with secondary adrenal insufficiency may have other hormone deficiencies which could impact on QoL. However, data from previous studies are inconsistent and while some impact was observed in a Norwegian study of patients with Addison’s disease [13
], another study [14
] showed that the impairment in health-related subjective health status in AI patients is largely independent of concomitant diseases.
More than half of the AI patients needed to alter their physical activity and many needed to change their social life, work life or family life due to their illness. The level of impact on social life is in line with data from another international survey, conducted in 2003, in which one-third reported that their condition impacted on their ability to participate in social activities [29
]. A Dutch patient survey reports similar impact on lifestyle [5
]. Detailed questions on fatigue were included in the current survey as fatigue is the most commonly reported subjective health-related problem in AI [5
]. This survey showed that 57% of the participants experienced fatigue in the morning as a problem and 65% reported fatigue during the day to be a problem. This response is in some contrast to the general perception that morning fatigue is a much larger clinical problem than fatigue during the day in patients with AI who have low or undetectable serum morning cortisol levels when using hydrocortisone BID or TID. Fatigue was more common in secondary AI than in primary AI and often necessitated changes in daily activities or changes in dose or the timing of dosing.
The current survey demonstrated a high absenteeism from work or school. More specifically, 4 of 10 patients reported absenteeism from work or school due to AI in the last 3
months and one third of those reported more than 3
weeks’ absence. Furthermore, 17% of the participants did not consider themselves to be fit to work. Among those who considered themselves fit to work, 28% worked part-time instead of full-time. These data are similar to those of a survey conducted across the UK, Canada, Australia and New Zealand (n
], in which over 10% of the respondents reported that they were unable to work compared with 1% in the matched control group. Moreover, in the study by Hahner et al. [14
], 18% of the AI patients (primary and secondary) did not work vs. 4% in the general population. In a Norwegian study, working disability amounted to 26% among patients with primary AI vs. 10% in the general population [13
Patients with AI are educated to increase their glucocorticoid dose in stressful situations and in association with other illnesses. This survey showed that 60-75% of the patients increased their replacement dose due to illness every month. The high rate of hospitalizations in this survey (38% of the patients had been hospitalized at least once in the last year) is in line with the Dutch survey in which 3 of 10 patients had been hospitalized [5
]. The reported reason for hospitalization was adrenal crisis, vomiting or an acute infection in 17% of the patients. As a comparison, the incidence rate of adrenal crises was 6.3 per 100 patient years in a study by Hahner et al. [31
]. The reason for this discrepancy is most likely the differences in methods of collecting data and that the definition of adrenal crisis is not the same, e.g. only cases of hospitalization necessitating i.v. glucocorticoid administration were counted as adrenal crises in the study by Hahner.
Because of the relatively small disease population, age and gender were not included in the questionnaire in order to protect personal integrity and anonymity. Internet use and behaviours linked to it are hypothetical confounding factors in the interpretation of the survey results. Patients who seek information about their disease usually tend to be more active than other patients, which can also affect the results. Despite the fact that congenital adrenal hyperplasia (CAH) constitutes one form of primary AI, it would have been interesting to analyse data on this patient group separately as recent data published by Arlt et al. (2010) showed significantly impaired health status and adverse metabolic and skeletal health in adult CAH patients [32
], however, data were not separately collected for patients with CAH in this survey.