Dosage and Duration of Methylprednisolone Therapy Affect the Occurrence of Cushing Habitus in Patients with Systemic Lupus Erythematosus.

CONTEXT: Systemic lupus erythematosus (SLE) is a multisystem disease with very diverse developments. Corticosteroid is mostly used for the treatment of SLE as antiinflammatory and immunosuppressant, but its long-term use and high dose can cause the side effects such as Cushing habitus. AIM: Analyze the risk factors of Cushing habitus occurrence in patients with SLE comprising pulse dose, duration of therapy, daily dose, and total dose of methylprednisolone. SETTINGS AND
DESIGN: Case Control study.
MATERIALS AND METHODS: 40 patients with SLE treated at Rheumatology outpatient clinic at Hasan Sadikin Hospital in Bandung was conducted. Each of these patients were divided into case and control groups. The design of this study was a case control study, the data was retrieved from medical record of patients with and without cushing habitus. STATISTICAL ANALYSIS: Chi-squared test was used to test the relationship between independent variables followed by linear logistic regression analysis to determine the influence of the most influential variable in causing Cushing habitus.
RESULTS: The results of this study showed that the use of total dose of methylprednisolon (> 8040 mg) has a significant effect on the incidence of Cushing habitus p = 0.029; odds ratio [OR] = 3.55). In addition, daily dose of methylprednisolone >9.4 mg has a significant effect on Cushing habitus (p = 0.012; OR = 2.98).
CONCLUSION: Significant relationship between daily dose and total dose of methylprednisolone on the occurrence of Cushing. Copyright:

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of autoantibodies to the cell nucleus and involves many organ systems.[1] The disease has a fairly high mortality rate, particularly affecting women of childbearing age. Factors affecting SLE pathophysiology are genetic, immunological, hormonal, and environmental.[2] SLE morbidity is associated with the quality of life and life expectancy of the patient. The comorbidity of patients with SLE increases the risk of cardiovascular disease, stroke, osteoporosis, and infectious diseases.[3]

The reported prevalence of SLE worldwide is 20–70 cases per 100,000 population, whereas in the United States it is 52 cases per 100,000 population.[4] Epidemiological data of SLE in Indonesia have not covered all regions; however, 2012 data at Cipto Mangunkusumo Hospital, Jakarta found 1.4% SLE of total patient visits in the Rheumatology polyclinic. Meanwhile, at Hasan Sadikin Hospital Bandung, there were 291 (10.5%) patients with SLE who visited to Rheumatology outpatient clinic.[2]

Corticosteroid is a major therapy for SLE because it can control the activity of SLE disease as an immunosuppression and anti-inflammatory agent. Corticosteroid therapy in SLE is used for long periods; therefore, some side effects may arise. The side effect of the corticosteroid depends on the duration of therapy and dose of corticosteroid itself. One of the most common side effects of corticosteroid is Cushing habitus symptom comprising moon face, striae, buffalo hump, and central obesity.[5] Cushing habitus morbidity is associated with central obesity, insulin resistance, diabetes mellitus, hypertension, hyperlipidemia, osteoporosis, and cardiovascular risk.[6]

This study aimed to analyze the risk factors for developing Cushing habitus in patients with SLE using corticosteroid. The risk factors analyzed in this study were pulse dose of methylprednisolone, daily dose of methylprednisolone, total dose of methylprednisolone, and duration of methylprednisolone therapy. The occurrence of side effects because of the pulse dose of methylprednisolone reached more than 50%. Common side effects are Cushing habitus such as moon face, but no worse than patients with daily methylprednisolone therapy.[7] The daily dose of 5 mg corticosteroids affect the occurence of cushing habitus, and there is an increase in occurence when the dose is more than 7.5 mg equivalent to prednisone.[8]

Materials and Methods

Study design and sample

Subjects in this study were lupus patients who visited the Rheumatology outpatient clinic of Hasan Sadikin Hospital Bandung during 3 months. The inclusion criteria of the study were patients who met the ACR (The American College of Rheumatology)/SLICC (Systemic Lupus International Collaborating Clinics) diagnostic criteria for SLE, patients who were 18 years old or above, patients who were willing to participate into the study by signing informed consent, patients who received at least 1 month of corticosteroid therapy, and patients who still consumed corticosteroid at the time this study. The exclusion criteria of the study were SLE patients with adrenal hyperplasia and patients who had incomplete data of treatment on their medical records. Interview was conducted to each consecutive SLE patients who came to the clinic. Occurrence of Cushing habitus was confirmed by the rheumatologist and the subjects were divided into case group (having Cushing habitus) and control group (without having Cushing habitus). Then the history of taking corticosteroid was traced from the patient’s medical record. Ethical approval for this study was obtained from Health Research Ethics Committee Faculty of Medicine, University of Padjadjaran (Protocol no.1212/UN6.C10/PN/2017).

The design of this study was a case control study, the data was retrieved from medical record of patients with and without cushing habitus. Data from SLE patients with cushing habitus is used as case group, whereas data from patients without cushing habitus is used as control group. Cushing habitus criteria, such as moon face, striae, buffalo hump, and central obesity, have been clarified by a consultant rheumatologist at Rheumatology polyclinic. Patients who were included in the study then interviewed about the dose of methylprednisolone consumed during patient’s undergoing SLE therapy as well as tracking medical records from the patient’s medical record and pharmacy records about the dose of methylprednisolone consumed by patients.

Sample calculation

The sample size calculation for this study was as follows:

where n is the number of sample, I is an independent variable, and p is the prevalence of event.

The number of samples required was 40 patients in the case group and 40 patients in the control group. Addition of 10% of the sample is needed to anticipate dropouts.

Outcome of this research is expected to be a suggestion for the health-care workers, especially doctors and pharmacists, in order to organize the methylprednisolone therapy in patients with SLE, and the importance of giving counseling, information, and education to the patients who undergo the methylprednisolone therapy.

Data analysis

Statistical analysis was carried out by using a chi-squared test followed by logistic regression analysis to determine the most influential risk factors responsible for Cushing habitus. Logistic regression analysis was conducted using backward method because in the initial model there was no significant risk factor, whereas in the final model there were two significant risk factors.

Results

Subject’s characteristics

There were total 109 subjects who were eligible and agreed to participate the study. Among them, 80 were included subjects and 29 were excluded subjects. The research subject’s characteristics were assessed by age at study conducted, duration of having SLE, age at SLE diagnosis, education, occupation, and ever being hospitalized after SLE diagnosis [Table 1]. Data normality was checked by using the Saphiro–Wilk test and Mean represents the normal distribution of data.

Table 1

Basic characteristics of research subject

	Cushing n = 40	Non-Cushing n = 40	p value
Gender	40 (100)	40 (100)
Age (years)
Mean ± SD	30 ± 7	38 ± 10	<0.001a*
Education
Elementary school	2 (5.0)	2 (5.0)	0.127c
Junior high school	13 (32.5)	6 (15.0)
Senior high school/vocational high school	21 (52.5)	20 (50.0)
D1/D3	1 (2.5)	6 (15.0)
S1	3 (7.5)	6 (15.0)
Occupation
Unemployed	3 (7.5)	2 (5.0)	0.057c
Civil servant	0 (0.0)	3 (7.5)
Private employees	2 (5.0)	6 (15.0)
Self-employed	3 (7.5)	0 (0.0)
Teacher	4 (10.0)	4 (10.0)
Housewife	24 (60.0)	25 (62.5)
Student	4 (10.0)	0 (0.0)
Ever being hospitalized
Yes	17 (42.5)	13 (32.5)	0.356c
No	23 (57.5)	27 (67.5)
Age when SLE diagnosis (years)
Mean ± SD	26 ± 7	34 ± 10	<0.001a*
SLE duration (months)
Median (range)	35 (3–170)	28 (1–156)	0.733b

SD = standard deviation, n = number, SLE = systemic lupus erythematosus, % = percentage

at-test

bMann–Whitney test

cChi-squared test

*Significant at p < 0.05

Occurrence of Cushing habitus

Cushing habitus is a symptom of Cushing syndrome that does not require laboratory results to determine its criteria.[9] Cushing habitus manifestations observed in this study were moon face, striae, buffalo hump, and central obesity [Figure 1].

Figure 1

Manifestation of Cushing habitus

Daily and total doses affect the occurrence of Cushing habitus

Median duration of Cushing group was 35 months, whereas in non-Cushing group it was 27 months. The group of cases that receive methylprednisolone get longer therapy than the control group [Table 2].

Table 2

Risk factors for of Cushing habitus occurrence

Variable	Cushing	Non-Cushing	p value
	n = 40	n = 40
	Median (IQR)	Median (IQR)
Duration of therapy (months)	35 (15–57)	27 (14–67)	0.784
Daily dose (mg)	12.4 (6.9–15.5)	8.0 (5.2–10.8)	0.013*
Total dose (mg)	9253 (6396–13584)	5717 (3874–10558)	0.020*
Pulse MP dose	0 (0–3000)	0 (0–1500)	0.399

IQR = inter quartile range

Analysis done by using Mann–Whitney test

*Significant at p < 0.05

The median daily dose of Cushing group habitus was 12.4 mg, whereas the median daily dose of control group was 8 mg. This indicated that subjects received methylprednisolone in higher daily dose than subject of control group (p = 0.013) [Table 2].

Total median dose of the Cushing habitus group was 9253 mg, whereas total median dose of non-Cushing habitus group was 5717 mg. A value of p = 0.020 was considered statistically significant [Table 2].

The median pulse dose in both Cushing habitus and control groups was 0 because of the small number of patient who receive the therapy. There were only two subjects in the case group and four subjects in the control group who took pulse dose of methylprednisolone. The median, 0, means the subject did not receive pulse dose of methylprednisolone therapy [Table 2].

Characteristics of Cushing habitus risk factors

The total number of research subjects was 80 people, with a median duration of therapy 29 months, a minimum duration of 3 months, and a maximum duration of 170 months. The median of all subject’s daily dose was 9.4 mg with the lowest daily dose of 1.1 mg and the highest daily dose of 38.1 mg. The median total dose of all subjects was 8040 mg with the lowest total dose of 1667 mg and the highest of 34.824 mg. The median pulse dose was 0 mg with the lowest pulse of 0 mg and the highest pulse dose of 3000 mg [Table 3].

Table 3

Cutoff based on the risk factor of Cushing habitus

Variable	Total n = 80
	Median (IQR)	Range
Duration of therapy (months)	29 (15–60)	3–170
Daily dose (mg)	9.4 (6.5–13.3)	1.1–38.1
Total dose (mg)	8040 (4870–12515)	1667–34824
Pulse MP dose	0	0–3000

IQR = inter quartile range

The correlation of risk factors with the Cushing habitus occurrence

Twenty-two subjects in the Cushing habitus group underwent long-term methylprednisolone therapy for more than 29 months, whereas only 18 were in the control group. The p values for the bivariate analysis of treatment variables were not found to be significant (p = 0.371; odds ratio [OR] = 1.49; confidence interval [CI] 95% = 0.62–3.61). There is no significant difference among pulse [Table 4].

Table 4

Correlation analysis of risk factors with the occurrence of Cushing habitus on subjects of SLE

Variable	Cushing n = 40n (%)	Non-Cushing n = 40n (%)		Crude OR (95% CI)
Therapy duration
>29 months	22 (55.0)	18 (45.0)	0.371	1.49 (0.62–3.61)
≤29 months	18 (45.0)	22 (55.0)
Daily dose
>9.4 mg	24 (60.0)	16 (40.0)	0.074	2.25 (0.92–5.50)
≤9.4 mg	16 (40.0)	24 (60.0)
Total dose
>8040 mg	25 (62.5)	15 (37.5)	0.025*	2.78 (1.12–6.87)
≤8040 mg	15 (37.5)	25 (62.5)
Pulse MP (methylprednisolone) dose
>0	4 (10.0)	2 (5.0)	0.675	2.11 (0.36–12.24)
≤0	36 (90.0)	38 (95.0)

Cutoff based on median of total sample

Analysis done using chi-squared test

*Significant at p < 0.05

Correlation of Cushing habitus and research variables

Multivariate analysis of independent variables was associated with Cushing habitus using logistic regression analysis. The independent variables include duration of therapy, daily dose, total dose, and pulse dose. The results of multivariate analysis are presented in Table 5.

Table 5

Multivariate analysis of Cushing habitus risk factors in SLE subjects

Variable	Total n = 80
	Adjusted OR (95% CI)	p value
Daily dose (>9.4 mg)	2.98 (1.12–7.95)	0.029*
Total dose (>8040 mg)	3.55 (1.33–9.46)	0.012*

The index (*) shows that p value is significant

Discussion

Table 1 shows that the average age of the subjects in the case group was 30 years old, whereas the mean age of subjects in the control group was 38 years old. The median of SLE duration was 35 months with a minimum duration of at least 3 months and a maximum duration of 170 months. Most of the subjects had high-school education backgrounds in both study groups. Regarding the occupation, most of the subjects worked as housewives. The mean age when SLE diagnosed in the case group was 26 years old, whereas the mean age in the control group was 34 years old (p < 0.001).

The most common manifestation of Cushing habitus was moon face occurred in 21 SLE patients (52.5%) and striae occurred in 28 SLE patients (70%) [Figure 1]. One patient could experience several Cushing habitus manifestations in the same time [Figure 2]. Cushing habitus manifestations that often appear were moon face and striae.

Figure 2

Number of Cushing habitus manifestation

Twenty-two subjects in the Cushing habitus group underwent long-term methylprednisolone therapy for more than 29 months, whereas only 18 were in the control group. The p values for the bivariate analysis of treatment variables were not significant (p = 0.371; OR = 1.49; CI 95% = 0.62–3.61).

The total daily dose >9.4 mg was found to be significant (p = 0.074; OR = 0.074; CI 95% = 0.92–5.50). The total daily dose >8040 mg was also found to be significant (p = 0.025; OR = 2.78; CI 95% = 1.12–6.87). However, no significance was found for pulse dose therapy [Table 4].

Multivariate analysis shows that of the four independent variables studied, only two variables have significant values [Table 5]. Variables that have significant values are daily dose and total dose.

The daily dose had a significant effect in increasing the occurrence of Cushing habitus (p = 0.029; OR = 2.98; CI 95% = 1.12–7.95). This suggested that daily dosing of methylprednisolone >9.4 mg would give 2.98 times the occurrence of Cushing habitus. The dose of methylprednisolone equivalent to prednisone was 11.75 mg.

The total dose had an odds ratio of 3.55 with p = 0.012, indicating that the total dose had a significant effect on increasing the incidence of Cushing habitus. Subjects who received a total dose of >8040 mg had a risk of 3.55 times greater Cushing habitus incidence than subjects who received total dose <8040 mg.

The subject of this research consisted of 80 patients, all of the sample was woman. Reported by Yanih (2016), the prevalence of SLE in women is higher than in men, with ratio of 9:1.41 The age of the research subjects while participating in the study was, in average, 30 years in the Cushing habitus group and 38 years in the non-Cushing habitus group. The age of the subjects while diagnosing lupus was, in average, 28 years in the non-Cushing habitus group and 35 years in the Cushing habitus group. This suggested that majority of lupus patients were diagnosed at a productive age. SLE usually strikes at the age of 15–45 years.[1011] More than half of the subjects in both groups had senior high-school education. Based on the occupation, housewife is the major occupation (60%).

The treated SLE patients were flare patients. The number of treated patients in the Cushing habitus group was 42%, whereas in the non-Cushing habitus group the number of patients treated was 32.3%. Comparing the number of subjects who hd ever undergone hospitalization from both groups, the Cushing habitus group had a higher number of subjects than the non-Cushing habitus group.

Cushing habitus is a partial manifestation of Cushing syndrome. In the case of Cushing syndrome, both endogenous and exogenic, the sign of Cushing habitus is common in patients and it is an early sign of Cushing’s syndrome, such as moon face, central obesity, buffalo hump, and striae.[12]

The case group (Cushing habitus) comprising 40 patients with the highest occurrence of Cushing habitus is striae occurred in 28 patients, moon face occurred in 21 patients, obesity occurred in 4 patients, and buffalo hump occurred in 4 patients. Striae is a manifestation of Cushing habitus that often appears at the beginning.[13]

The most manifestation of Cushing habitus emerged in this study was striae. Corticosteroid degrades total skin collagen in patients so that collagen is difficult to stretch that causes striae. The histopathology of striae conditions indicates the damage caused by the separation of collagen bonds and small fragments of elastic fibers.[1314]

The next most manifestation is the moon face followed by central obesity. Moon face and central obesity are manifestations of Cushing habitus that have a high incidence rate. In accordance with Bernard’s research, moon face and central obesity emerged as a manifestation of Cushing syndrome with a percentage of 80%–90%.[14] Central obesity and moon face are the classic signs of Cushing’s symptoms. The use of corticosteroids is associated with weight gain. This is associated with increased appetite and dyspepsia so that the patient copes with increased food intake. The redistribution of fat produces Cushing habitus, which includes moon face, central obesity, and buffalo hump.[14]

Most patients who experience Cushing habitus are patients who have received high doses of corticosteroid or long-term corticosteroid. Corticosteroid in various dosage forms has glucocorticoid activity. Corticosteroid is usually well-absorbed at any given site. Aerosol, topical, and intra-articular administration also contribute to the development of Cushing syndrome.[15]

Natural glucocorticoids such as cortisone and cortisol and their synthetic derivatives such as prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and others are used clinically and have potential side effects. The most potent drugs that cause Cushing syndrome is not known for certain because there are many factors that cause the syndrome. Characteristics of the steroid classes associated with the syndrome are the formulation used, pharmacokinetics, glucocorticoid receptor affinity, biological potential, and duration of action. Pharmacokinetic factors include binding affinity for cortisol binding globulin (CBG) and other plasma proteins, metabolic inactivation, and plasma half-life. Generally, synthetic glucocorticoids do not have a strong bond to CBG, but bind to albumin or as free steroids. In contrast, synthetic glucocorticoids have a much higher affinity for glucocorticoid receptors than cortisol. The potential and duration of action are also influenced by the rate of absorption and metabolism. Potential assessment generally does not take into account those factors.[15]

The development of Cushing signs and symptoms is generally associated with dose and duration of treatment, so that low-potential agents with short half-life (hydrocortisone and cortisone) may cause Cushing effects if given in moderate amounts. The estimated dose and timing of Cushing syndrome are difficult to determine due to the factors mentioned, different formulations and administration, as well as the factors of each patient with different sensitivity to glucocorticoids.[15]

Some symptoms due to excess glucocorticoids generally arise relatively fast. Psychological effects, insomnia, and increased appetite may occur within hours. Meanwhile, Cushing symptoms that affect the appearance or physical arise within weeks or even months, as in the development of osteoporosis. There is a tremendous variability between individuals with regard to dosage. Although supraphysiologic doses are usually required before the patient showing Cushing effect, some patients, especially those taking glucocorticoids after renal transplantation, may develop Cushing symptoms physically with chronic administration of only 5 mg/day of prednisone.[15]

Corticosteroids have long been used for anti-inflammatory and immunosuppression therapy since 60 years ago. The use of high dose corticosteroids was first reported in 1969 when it was successfully used to prevent kidney transplant rejection.[16]

The common corticosteroid used in pulse therapy is methylprednisolone. Methylprednisolone is a corticosteroid with intermediate action with biological half-life of 12–36h. Methylprednisolone is a potent corticosteroid with a lower mineralocorticoid effect than its glucocorticoid effect.[16]

The purpose of pulse therapy is to accelerate and improve efficacy as well as decrease the long-term steroid use requirements. The use of high-dose corticosteroids may actually provide a corticosteroid-saving effect.45

In patients with SLE, methylprednisolone pulse therapy is used in lupus nephritis patients and recent studies suggest that methylprednisolone pulse therapy is used in SLE patients with flares.[16]

The incidence of adverse effects on methylprednisolone pulse therapy reached more than 50%. Cushing syndrome side effect, such as moon face, in patients with pulse dose is not as worse as in those who take single dose methylprednisolone.[16]

Statistics showed that dosing of pulse dose methylprednisolone did not significantly increase the occurrence of Cushing habitus (p = 0.682; CI 95% = 0.23–9.54). Although the number of subjects given pulse therapy mostly was 4 in Cushing group, the number of subjects given pulse therapy in the non-Cushing group reached to 2. Pulse dosing may potentially increase the occurrence of Cushing but as subjects receiving pulse therapy were only 6 of the 80 patients, the results were insignificant.

The daily dose of corticosteroid is 5 mg which affected the occurence of Cushing habitus. This condition will increase if administered dose was more than 7.5 mg (equivalent prednisone) with the manifestation of striae, moon face, and weight gain.39 This finding is consistent with that of Huscher et al.,[8] who stated that the prevalence of Cushing habitus would increase with the increasing doses of corticosteroids at 4.3% at doses <5 mg and then increased to 15.8% at doses of 5–7.5 mg and increased again to 24.5% at doses >7.5 mg.

The statistical results represented that the total dose has a significant effect on the occurrence of Cushing habitus (p = 0.012; OR = 3.55; CI 95% = 1.33–9.46), meaning that the administration of total dose of methylprednisolone >8040 mg will give 3.55 times the occurrence of Cushing habitus.

The limitation of this study is that it inform the relationship of total dosage and the occurrence of Cushing habitus. The duration of therapy did not significantly affect the occurrence of Cushing habitus (p = 0.595; CI 95% = 0.31–7.68), although statistics signified that prolonged treatment of SLE methylprednisolone for more than 29 months would increase 1.54 times the risk of Cushing habitus.

Conclusion

The results of this study indicated a significant relationship between daily dose and total dose of methylprednisolone on the occurrence of Cushing habitus, but no significant relationship was found between duration of therapy and pulse dose of methylprednisolone with the occurrence of Cushing habitus. This study resulted in a daily cutoff dose and a total dose of methylprednisolone on the risk of Cushing habitus occurrence on SLE subjects. Daily dose of methylprednisolone >9.4 mg will increase the risk of the occurrence of Cushing habitus as high as 2.98 times. Administration of total dose of methylprednisolone >8040 mg will increase 3.55 times the risk of Cushing habitus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.