Graft versus host disease (GvHD) is a serious and common complication of allogenic haematopoietic stem cell transplant (Lee and Flowers, 2008). Chronic GvHD has a negative impact on morbidity and quality of life, as well as non-relapse mortality (Pidala et al, 2009). Corticosteroids are considered standard care for initial treatment of chronic GvHD but a significant proportion of patients will need long-term steroid treatment for control of GvHD (Alfred et al, 2017). Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy that is an accepted second-line treatment in patients with steroid-refractory, steroid-dependent or steroid-intolerant GvHD and has shown efficacy in allowing steroid dose reduction and discontinuation in this cohort of patients (Alfred et al, 2017). The overall aim of ECP is to allow the reduction in corticosteroid dose, and the resolution of GvHD activity. Typically corticosteroids are stopped once a slow taper has taken place and there is no evidence of a flare of GvHD symptoms.
During ECP, mononuclear cells are collected, treated with a photosensitiser and exposed to ultra-violet light outside of the body before being re-infused back into the patient (Woltz et al, 2006). The mechanism of ECP treatment is not fully understood but it induces apoptosis of lymphocytes, among other immune cell subsets, including activated T-cells (Peritt, 2006). These cells are responsible for influencing immune homeostasis (Peritt, 2006) and when they are re-infused, it induces a selective immunological response enabling a lower dose of steroid to be effective. It is important to note that other mechanisms of action for ECP have been described (Heshmati, 2003).
Adrenal cortical insufficiency is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids leading to a severe and potentially life-threatening condition due to the central role of these hormones in energy release, and salt and fluid homeostasis (Bornstein et al, 2016). Adrenocortical insufficiency results in a decrease in feedback to the hypothalamic–pituitary axis and subsequent enhanced stimulation of the adrenal cortex by elevated levels of plasma adrenocorticotropic hormone (ACTH). Following disruption of adrenal mineralocorticoid synthesis, renin release by the juxtaglomerular cells of the kidneys increases (Bornstein et al, 2016). The signs of adrenocortical insufficiency are mainly based on the deficiency of gluco- and mineralocorticoids, which results in weight loss, orthostatic hypotension due to dehydration, hypernatremia, hyperkalaemia, changes in blood count (anaemia, eosinophilia, lymphocytosis), and hypoglycaemia. Enhanced secretion of ACTH and other pro-opiomelanocortin peptides often leads to the characteristic hyperpigmentation of the skin and mucous membranes. The symptoms of adrenocortical insufficiency are rather nonspecific and include weakness, fatigue, musculoskeletal pain, abdominal pain, depression, and anxiety. As a result, the diagnosis is frequently delayed, resulting in a clinical presentation with an acute life-threatening adrenal crisis.
The most common cause of drug-induced adrenal insufficiency is the suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoid doses ≥5 mg prednisolone equivalent for more than 4 weeks, irrespective of mode of delivery (topical, inhaled, oral or injected) (Bancos et al, 2015). This poses a significant risk to GvHD patients, who are frequently prescribed notably higher doses of prednisolone for periods of time much longer than 4 weeks (Stewart et al, 2004). An adrenal crisis remains a threat to life, but, with increased patient awareness of the signs and symptoms, and the implementation of preventive measures, clinical outcomes could be improved (Bancos et al, 2015).
Aim
The aim of this case review was to ascertain the number of patients with adrenal insufficiency among those who have received ECP for GvHD and discontinued steroid treatment. ECP is a treatment that has no impact on adrenal insufficiency. An initial pilot study was undertaken, covering a period of 6 months, where patients were screened for potential adrenal insufficiency before stopping steroids. The pilot was found to be successful, as it discovered patients with adrenal insufficiency who could have been missed. Therefore the case review continued and more patients were monitored. A review took place 2 years after starting the pilot.
The ACTH stimulation test, also termed cosyntropin test or short Synacthen test (SST), is commonly used for the diagnosis of adrenal insufficiency. The test can be performed at any time of the day by drawing blood at baseline and 30 or 60 minutes after parenteral administration of 250 μg of ACTH 1-24 (Synacthen) and measuring serum cortisol levels. In some Trusts local policy is to use the so-called low-dose ACTH test employing 1 μg of ACTH; however, this still represents a supraphysiological stimulus and no advantage of this test has been demonstrated convincingly. In addition, commercially available ACTH ampoules contain 250 μg ACTH1-24, rendering a dilution impractical and too inaccurate for routine use (Bancos, 2015). This study used an SST for screening eligible patients.
Methods
Once a patient had been assessed by the clinical lead for photopheresis and deemed suitable to stop corticosteroids, the SST was planned for the patient's next visit, which usually occurred within 4 weeks.
Under local protocol, a baseline serum sample was taken for cortisol measurement; 250 µg Synacthen in 1 ml (adult dose) was administered via peripheral cannula by slow intravenous injection (over 2-3 minutes) by a registered nurse. Two further blood samples were then taken for cortisol analysis at 30 minutes and then 60 minutes following administration of the drug. SST should always use cut-offs derived for the specific assay in use in the laboratory. For the assay currently in use at the Trust the 30-minute and 60-minute cortisol cut-off is 470 nmol/litre. The 60-minute sample is used to look for a delayed response to the Synacthen.
Results
Over the review period of 23 months, a total of 23 patients were tested. Characteristics of these patients are outlined in Table 1. All patients who would be eligible for the test were tested, no patient was excluded. Of the patients tested, seven (30%) were found to have an inadequate response to the SST, while one further patient (4%) was found to have a delayed response. All these patients were subsequently referred to the endocrine team for further investigation.
| Patient characteristic | n | |
|---|---|---|
| Sex | Male | 19 |
| Female | 4 | |
| Age |
Under 40 | 4 |
| 40–59 | 11 | |
| Over 60 | 8 | |
| Diagnosis* | Acute leukaemia | 9 |
| Chronic leukaemia | 4 | |
| Lymphoma | 6 | |
| Myeloma | 2 | |
| Anaemia | 1 | |
| Types of transplant† | Matched unrelated donor | 11 |
| Sibling matched | 6 | |
| Donor lymphocyte infusion | 4 | |
| Immunosuppressive medication‡ | Cyclosporine | 14 |
| Tacrolimus | 2 | |
| Mycophenolate mofetil (MMF) | 4 | |
| Onset of GvHD after transplant |
1 month or less | 4 |
| Over 1 month up to 3 months | 8 | |
| Over 3 months up to 6 months | 5 | |
| Over 6 months up to 1 year | 5 | |
| Over 1 year | 1 | |
| Number of weeks on steroids | Up to 50 weeks | 4 |
| 51–100 weeks | 9 | |
| 101–150 weeks | 2 | |
| 151–200 weeks | 3 | |
| Over 200 weeks | 5 | |
| Number of weeks on ECP before taper started |
1–4 weeks | 7 |
| 5–8 weeks | 12 | |
| 9–12 weeks | 2 | |
| Over 12 weeks | 2 | |
ECP: extracorporeal photophoresis GvHD: graft vs host disease
Discussion
Adrenal insufficiency is a known complication of long-term steroid use. Left undiagnosed it can lead to significant clinical impact, particularly in times of physiological stress such as infections. No patients in this cohort had any signs or symptoms of adrenal insufficiency, however, as it is a known side effect of steroid treatment the decision was made to be proactive and test patients once steroid treatment had been discontinued, meaning potential problems could be picked up at an early stage. On initial inspection of the patient data no one factor—patient's original diagnosis, type of transplant, sub type of GvHD, steroid dose over time or length of time taking the steroids—had any impact on determining who was at risk of adrenal insufficiency. Statisticians examined the relationship between dosage and adrenal function and found by separating the data into quartiles by dosage, including total dose and average dose (Figure 1) and duration, that there were patients in all groups who had an inadequate response. Even among the patients who had been on a lower dose and/or for a shorter duration, some seemed to have an inadequate response. Therefore statistical analysis could not find a predictive relationship based on dosage or duration. This shows that it is important that all patients discontinuing steroids should be tested, no matter the dose or length of time on steroids. However, this is a small group of patients and ideally a bigger sample may present a more complete patient population. In the future, based on the patients' clinical data, a prediction could be made of the likelihood of adrenal insufficiency based on dosage or duration of treatment.
Synacthen costs on average £38 per dose, which is inexpensive compared with the cost of treating a patient in adrenal crisis. Therefore, the authors would argue it is cost-effective to perform a simple test to identify patients with adrenal insufficiency at an early stage, rather than risk delayed diagnosis and a patient presenting in adrenal crisis. The patient will benefit from medical support and medication to prevent a crisis, and it will empower the patient to better understand the health condition they are experiencing.
Conclusion
Although only a small number of patients were included in this study, it has highlighted the importance of testing the adrenal reserves of all patients with chronic GvHD whose steroid treatment is being discontinued while undergoing photopheresis treatment. In this group, 35% of patients (8/23) potentially had decreased cortisol production in times of stress, which, if left unidentified, and therefore without preventive steps being taken, would have left them vulnerable to a life-threatening hypo-adrenal crisis. These patients were referred to the local endocrinology team for further evaluation of the clinical relevance of this finding and to instigate treatment if deemed appropriate. On the basis of these results the unit continues to test all patients once steroids have been stopped. This article will hopefully encourage other units to test patients and prevent a life-threatening condition from occurring.