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Pneumologie 2025; 79(03): 202-205
DOI: 10.1055/a-2510-9851
Letter to the Editor

Glucocorticoid-Induced Adrenal Insufficiency in Sarcoidosis Patients with Long-term Glucocorticoid Therapy

Roman Düvel
1   Herzzentrum des Universitätsklinikums Bonn, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
,
Vanessa Marggraf
2   Internal Medicine, Hausarztzentrum Rheinbach, Rheinbach, Germany
,
Carmen Pizarro
1   Herzzentrum des Universitätsklinikums Bonn, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
,
Leonie Biener
1   Herzzentrum des Universitätsklinikums Bonn, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
,
Wiebke Fenske
3   Department of Internal Medicine I – General Internal Medicine, Endocrinology and Diabetology, Gastroenterology and Hepatology, BG University Hospital Bergmannsheil, Bochum, Germany
,
Charlotte Fries
3   Department of Internal Medicine I – General Internal Medicine, Endocrinology and Diabetology, Gastroenterology and Hepatology, BG University Hospital Bergmannsheil, Bochum, Germany
,
Georg Nickenig
1   Herzzentrum des Universitätsklinikums Bonn, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
,
Christian Grohé
4   Klinik für Pneumologie Evangelische Lungenklinik Berlin, Berlin, Germany
,
Dirk Skowasch
1   Herzzentrum des Universitätsklinikums Bonn, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
› Author Affiliations
Supported by: Sarkoidose-Netzwerk e. V.
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Sarcoidosis is a granulomatous multi-system disease of unknown aetiology [1]. 10–30 % of the chronic subpopulations require prolonged treatment [1], most commonly in the form of systemic glucocorticoids (GC), which are considered the first line treatment for symptomatic sarcoidosis patients [2] [3] [4]. Symptoms of sarcoidosis are often unspecific and include fatigue, arthralgia, muscle pain, general weakness, fever and anorexia. Of all general symptoms, fatigue poses the most prevalent clinical feature of sarcoidosis and is seen in nearly 70 % of patients [1] [5]. However, fatigue may also be caused by the suppression of the hypothalamic-pituitary-adrenal (HPA) axis as an inevitable effect of chronic exogenous glucocorticoid therapy [6]. This suppression can manifest as glucocorticoid-induced adrenal insufficiency (GI-AI), which is among the most common causes of cortisol deficiency [7]. Clinical symptoms of GI-AI are unspecific [8] and overlap with the aforementioned symptoms in sarcoidosis. To our knowledge, no data are available on the prevalence of glucocorticoid-induced adrenal insufficiency in sarcoidosis patients. Recently, patients with current or recent history of exogenous GC use presenting with signs and symptoms suggestive of adrenal insufficiency are classified as being at high risk of glucocorticoid-induced adrenal insufficiency and should, if they currently receive a dose of 5 mg prednisolone equivalent, be tested by measuring early morning serum cortisol 24 hours after the last dose of GCs [7]. Therefore, between March 2022 and May 2023 we prospectively evaluated 62 consecutive patients with histologically proven sarcoidosis receiving a GC dose of 5 mg or less prednisolone equivalent for the development of glucocorticoid-induced adrenal insufficiency. Study inclusion required informed written consent. The study was approved by the ethics committee of the University of Bonn.

All patients received adrenal assessment by measuring early morning serum cortisol based on recent recommendations [7] and similar to the PONENTE trial [9]. Blood samples were collected between 08:00 and 09:00 a.m. Patients were required to fast and to pause their morning glucocorticoid dose. The samples were analysed by the hospital’s own laboratory using the Roche Elecsys II assay. A cortisol < 100 nmol/L (< 3.6 µg/dl) confirmed GI-AI, a cortisol level between 100 and 270 nmol/L (3.6 to 9.8 µg/dl) indicated a possible GI-AI and in patients with a cortisol level > 270 nmol/L (> 9.8 µg/dl) GI-AI was unlikely [7]. Furthermore, clinical routine included the performance of lung function tests and the analysis of Angiotensin Converting Enzyme (ACE) and soluble interleukin-2-receptor (sIL2-R) from blood samples. In addition to these clinical markers, general data such as age, gender, prednisolone equivalent dose, treatment duration and chest radiographic staging (Scadding) were considered. Moreover, three symptom questionnaires were completed for further assessment. To quantify the severity of sarcoidosis symptoms and to identify distinct symptoms often displayed in sarcoidosis patients, the German translation of the King’s Sarcoidosis Questionnaire was used [10]. For the evaluation of fatigue, the Fatigue Assessment Scale (FAS) was employed [5]. Study participants received a copy of the translation from Therme Wien. Moreover, the AddiQoL-questionnaire was used to ascertain symptoms of adrenal insufficiency. Even though AddiQoL was developed for primary adrenal insufficiency [11], the majority of symptoms also applies to patients with glucocorticoid-induced adrenal insufficiency and, of all three questionnaires used, only AddiQoL specifically measures quality of life (QoL). Recent data suggests that impairment in Quality of Life in sarcoidosis patients may be influenced by fatigue rather than by worsening of lung function or disease progression [12]. The differences of metric variables between the two groups were assessed via unpaired t-test, or Welch-test if Levene-Test showed no homogenity of variances. For not normally distributed variables indicated by Kolomorov-Smirnov and Shapiro-Wilk, non-parametric Wilcoxon Rank-Sum Test was used. For categorical variables Fisher’s Exact Test or Fisher-Freeman-Halton Exact Test was performed.

A total of 62 patients completed assessments (55.9 ± 13.2 years, 43.5 % male, mean GC-dose 3.3 ± 1.8 mg prednisolone equivalent, 46.8 % in Scadding stage II). GI-AI was diagnosed in 8 /62 patients (12.9 %). More precisely, the basal cortisol level was < 100 nmol/l in 8 patients (12.9 %), 100–270 nmol/l in 10 patients (16.1 %), 270–350 nmol/l in 15 patients (24.2 %) and > 350 nmol/l in 29 patients (46.8 %). Patients with GI-AI presented a significantly longer duration of GC therapy (9.58 ± 13.66 years vs. 4.03 ± 6.71 years, p = 0.028) and a significantly lower pulmonary diffusion capacity, both in terms of carbon monoxide diffusion capacity (DLCO) (4.43 ± 2.02 ml/min/mmHg vs. 6.19 ± 2.15 ml/min/mmHg, p = 0.034; 46.63 ± 15.98 % vs. 67.98 ± 19.55 %, p = 0.005) and in terms of DLCO/alveolar volume (0.9 ± 0.3 ml/min/mmHg/l vs. 1.25 ± 0.26 ml/min/mmHg/l, p < 0.001; 58.13 ± 12.93 % vs. 83.3 ± 15.85 % , p < 0.001). All the other characteristics were similar ([Table 1]).

Table 1

Baseline characteristics of all patients (n = 62) besides a comparison between subgroups defined by adrenal function. Data are presented as mean ± standard deviation or n (%). Chest radiographic staging according to the classification of Scadding, The Score of the three questionnaires Fatigue Assessment Scale (FAS), Addison Quality of Life (AddiQoL) and King’s Sarcoidosis Questionnaire (KSQ) arises from the point totals of the individual questions. A higher FAS-score indicates greater fatigue, a lower AddiQoL-score is associated with lower quality of life and a lower KSQ-score displays more pronounced sarcoidosis symptoms.

Total group

Patients with glucocorticoid-induced adrenal insufficiency

Patients without glucocorticoid-induced adrenal insufficiency

p-value

Subjects

62

8 (12.9 %)

54 (87.1 %)

Demographics

Age [years]

55.9 ± 13.2

53.4 ± 19.7

56.3 ± 12.1

0.698 (Welch t)

Male

27 (43.5 %)

4 (50 %)

23 (42.6 %)

0.719 (Fisher)

Glucocorticoid treatment

Prednisolone equivalent dose [mg/d]

3.3 ± 1.8

3.8 ± 1.2

3.2 ± 1.9

0.557 (WRS)

Glucocorticoid treatment duration [years]

4.8 ± 8.0

9.6 ± 13.7

4.0 ± 6.7

0.028[*] (WRS)

Scadding stages

Scadding stage 0

4 (6.5 %)

0 (0 %)

4 (7.4 %)

0.454 (FFH)

Scadding stage I

11 (17.7 %)

1 (12.5 %)

10 (18.5 %)

 

Scadding stage II

29 (46.8 %)

3 (37.5 %)

26 (48.1 %)

Scadding stageg III

9 (14.5 %)

1 (12.5 %)

8 (14.8 %)

Scadding stage IV

9 (14.5 %)

3 (37.5 %)

6 (11.1 %)

Questionnaires

Fatigue Assessment Scale score

29.2 ± 8.6

28.9 ± 8.8

29.3 ± 8.7

0.833 (WRS)

Addison Quality of Life score

109.8 ± 26.1

104.8 ± 34.2

110.6 ± 25.0

0.699 (WRS)

Kingʼs Sarcoidosis Questionnaire score

137.5 ± 28.9

118.6 ± 26.9

140.3 ± 28.5

0.060 (WRS)

Laboratory testing

Angiotensin Converting Enzyme (ACE) [U/l]

41.5 ± 24.5

47.5 ± 12.9

40.6 ± 25.7

0.129 (WRS)

Soluble interleukin-2 receptor (sIL2-R) [ng/ml]

5.0 ± 2.9

5.3 ± 1.6

4.9 ± 3.1

0.378 (WRS)

Pulmonary function parameters

Forced expiratory volume in 1 second [l]

2.6 ± 1.0

2.5 ± 1.4

2.6 ± 0.9

0.793 (WRS)

Forced expiratory volume in 1 second [% predicted]

81.0 ± 20.9

75.1 ± 27.1

81.9 ± 19.9

0.396 (t)

Forced vital capacity [l]

3.1 ± 1.1

3.1 ± 1.5

3.1 ± 1.0

0.691 (WRS)

Forced vital capacity [% predicted]

76.4 ± 15.8

72.6 ± 20.8

77.0 ± 15.1

0.470 (t)

Total lung capacity [l]

5.4 ± 1.5

5.8 ± 1.7

5.3 ± 1.5

0.411 (WRS)

Total lung capacity [% predicted]

88.2 ± 16.4

93.0 ± 23.8

87.4 ± 15.2

0.374 (t)

Residual volume [l]

2.2 ± 0.9

2.6 ± 1.1

2.2 ± 0.9

0.360 (WRS)

Residual volume [% predicted]

105.7 ± 41.6

126.3 ± 52.9

102.6 ± 39.3

0.230 (WRS)

Diffusing capacity [ml/min/mmsHg]

5.9 ± 2.2

4.4 ± 2.0

6.2 ± 2.2

0.034[*] (t)

Diffusing capacity [% predicted]

65.2 ± 20.3

46.6 ± 15.9

67.9 ± 19.6

0.005[*] (t)

Diffusing capacity/alveolar volume [ml/min/mmHg/l]

1.2 ± 0.3

0.9 ± 0.3

1.3 ± 0.3

< 0.001[*] (t)

Diffusing capacity/alveolar volume [% predicted]

80.1 ± 17.6

58.1 ± 12.9

83.3 ± 15.9

< 0.001[*] (t)

* = p < 0.05, p < 0.05 was considered statistically significant


In the current study, the prevalence of GI-AI was at least 12.9 %. Due to a similar clinical presentation of sarcoidosis and GI-AI and the overlap in this patient population, only a biochemical assessment of adrenal function can enable correct diagnosis and treatment. As a consequence, patients with GI-AI should be substituted with hydrocortisone, and appropriately educated. Even prior to a possible development of GI-AI, current clinical practice guideline recommendations include patient education regarding risks of adrenal insufficiency especially when tapering glucocorticoid medication below the physiologic daily dose equivalent [6]. Recently, the PONENTE trial, which examined the glucocorticoid elimination of patients with severe asthma switching from oral corticoids to benralizumab, showed an even higher prevalence of adrenal insufficiency (27 % complete insufficiency) [9]. This may be partly attributed to the use of the 250 μg ACTH(1–24) test and to differences between the Beckman Access cortisol immunoassay and the Roche Elecsys II immunoassay [9]. Risk factors for the development of GI-AI are glucocorticoid formulation, dose and treatment duration [7] [9]. Morning serum cortisol can be employed to confirm the recovery of the HPA axis and can be used in patients on a physiologic daily dose equivalent aiming to discontinue glucocorticoid therapy [6]. Even while showing a slightly more severe disease, no dedicated predictor of GI-AI was identified in the present study. Therefore, the question arises, whether all sarcoidosis patients receiving a prednisolone equivalent dose of 5 mg or less should receive biochemical adrenal testing. Even asymptomatic patients may suffer from impaired adrenal function, which further complicates a preselection.

The present study has several limitations including the relatively small number of patients studied, the single-centre design, and the lack of additional longitudinal follow-up. The study did not include further evaluation of adrenal function via 250 μg ACTH(1–24) test. However, to the best of our knowledge, this is the first study that correlated GI-AI with its clinical presentation in patients with sarcoidosis.

In summary, a high proportion of sarcoidosis patients present unspecific symptoms, which can be attributed either to the systemic disease or the long-term therapy with systemic glucocorticoids. The management of glucocorticoid therapy is considered a general medical skill and requires the recognition of signs and symptoms of adrenal insufficiency [6]. Therefore, GI-AI should be considered in treatment of sarcoidosis patients receiving long-term glucocorticoid treatment.



Publication History

Article published online:
19 February 2025

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